HTAD accounts for ~20-25% of all thoracic aortic aneurysms and dissections.
Most individuals with HTAD do not have additional associated features (non-syndromic).
HTAD presents at a younger age and is more aggressive than other TAA.
Appropriate recognition of HTAD allows initiation of imaging surveillance in at-risk relatives.
A positive genetic test result can help guide pharmacotherapy, determine vascular regions which require ongoing imaging surveillance, influence surgical threshold, and allow for cascade testing of at-risk relatives.
In most families with HTAD, genetic testing does NOT identify the responsible genetic variant. Thus negative testing does not exclude HTAD and at-risk relatives would still need ongoing imaging surveillance.
Pharmacological management for those with TAA may include:
beta-blockers or angiotensin receptor blockers to limit aneurysmal dilation.
avoidance of medications and recreational drugs with potential vasoactive effect (e.g. triptans, cocaine).
Fluoroquinolones should be avoided where possible in anyone with or at risk for aortic aneurysms of any type because of the associated increased risk of aortic dissection.
Participation in competitive sports and isometric exercises are advised against.
Bottom line: Hereditary thoracic aortic disease (HTAD) accounts for 20-25% of thoracic aortic aneurysms and dissections. Most individuals with HTAD do not have additional associated features (non-syndromic). HTAD presents at a younger age and is more aggressive than other thoracic aortic aneurysms (TAA). Appropriate recognition of HTAD allows initiation of imaging surveillance in at-risk relatives. Genetic testing should be offered to individuals with TAA who have at least one of the following red flags:
Thoracic aortic dilation reported on imaging as mild or greater, at age <50y or <60y in the absence of hypertension
Thoracic aortic dissection at age <60y or <70y in the absence of hypertension
Positive family history
Pathogenic variant in a HTAD gene identified in a relative
Syndromic features e.g. features of Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos Syndrome (EDS)
Identification of a genetic etiology can help guide pharmacotherapy, determine vascular regions which require ongoing imaging surveillance, and influence surgical thresholds as these are lower for HTAD versus degenerative type aneurysms.
An uninformative (negative) genetic test result does not exclude HTAD and at-risk relatives would still need ongoing imaging surveillance.
Pharmacological management for those with TAA may include:
beta-blockers or angiotensin receptor blockers to limit aneurysmal dilation.
avoidance of medications and recreational drugs with potential vasoactive effect (e.g. triptans, cocaine).
Participation in competitive sports and isometric exercises are advised against.
Fluoroquinolones should be avoided where possible in anyone with or at risk for aortic aneurysms of any type because of the associated increased risk of aortic dissection.
What is heritable thoracic aortic disease (HTAD)?
Approximately 25% of thoracic aortic aneurysms (TAA) are heritable. The remainder are primarily caused by age and hypertension, some may have infectious/inflammatory or traumatic etiologies.
About 20% of individuals with hereditary TAA will have no additional associated features (non-syndromic) but will have a positive family history. Five percent of individuals with TAA will have a syndromic condition (e.g. Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos Syndrome (EDS)). These persons may be the first individual with this condition (de novo) in their family.
Individuals with HTAD typically present at a younger age and have more aggressive disease than individuals with degenerative TAA. However, the age of onset, even within members of the same family, can be variable. Both those assigned male and those assigned female at birth can be affected.
TAA are typically asymptomatic but can lead to aortic dissections. Emergency aortic repair is associated with a 50% mortality. Individuals diagnosed with a TAA prior to dissection can benefit from pharmacotherapy, lifestyle modification and, if required, elective surgical repair (associated with a 1-2% mortality rate).
What does the genetic test result mean?
Currently the decision to offer genetic testing is made in the setting of a genetics and/or cardiology consult. Click here to connect to your local genetics centre. Most genetic testing for HTAD is panel-based, where multiple genes are tested concurrently.
The detection rate of genetic testing for HTAD is approximately 20%, which means that 80% of individuals with HTAD will not receive an informative (positive) result.
Genetic test results can be positive (a causative pathogenic variant in a gene is detected), negative/uninformative (no genetic variants of clinical significance detected), true negative (an unaffected individual does not carry the familial causative genetic variant), or variant of uncertain significance (VUS, a genetic variant is detected however whether it is pathogenic or benign cannot be determined at this time). For more on genetic test results see the HTAD GECKO deep dive or GECKO resources on genomic test results.
Who to consider referring for a genetic assessment?
Consider referral for a genetic assessment for individuals with a:
Thoracic aortic dilation reported on imaging as mild or greater, at age <50y or <60y in the absence of hypertension
Thoracic aortic dissection at age <60y or <70y in the absence of hypertension
Thoracic aortic dilation reported on imaging as mild or greater, at any age in the presence of any of the following family histories in a 1st or 2nd degree relative:
TAA or thoracic aortic dissection
Sudden cardiac death at age <50y without a confirmed alternate etiology
Personal or family history of thoracic aortic dilation or TAA at any age, and features that suggest an underlying syndromic condition, such as:
Tall for family (or tall and from a family where individuals with aneurysms tend to be significantly taller than those without aneurysms)
Ectopia lentis (lens dislocation)
Spontaneous pneumothorax (particularly if recurrent)
Hypertelorism (wide-spaced eyes)
Bifid uvula
Hollow organ rupture e.g. uterus, colon
Spontaneous tendon rupture
Large and unprovoked bruising (prior to anti-coagulation)
Very translucent skin
Pectus carinatum or significant pectus excavatum
Scoliosis requiring bracing or surgery
Significant varicose veins at a young age
1st or 2nd degree relative in whom a pathogenic variant in one of the hereditary thoracic aortic disease (HTAD) genes has been identified (referral of 3rd degree relatives can be considered when intervening relatives are not available for or decline testing)
Surveillance and Management
Further details on surveillance and management can be found in the HTAD GECKO deep dive.
Individuals with HTAD should be referred to an aortic clinic (preferably) or to a cardiologist.
For those with HTAD and who have a TAA, management in terms of frequency of imaging, pharmacotherapy, vascular regions requiring ongoing imaging surveillance and surgical threshold will be influenced by the underlying gene (and sometimes the underlying variant). Pharmacotherapy typically includes a beta-blocker or an angiotensin receptor blocker to limit aneurysmal dilation. Participation in competitive sports is usually advised against and isometric exercises should be avoided. Some medications and recreational drugs with a potent vaso-active effect (e.g. triptans, cocaine) are discouraged.
All first-degree relatives of an individual with HTAD should have regular surveillance, unless they test negative for the familial causative genetic variant. The specific surveillance will depend on the underlying gene identified in the family. Referral to an aortic clinic (preferably) or to cardiology and genetics is recommended.
The question of when to initiate screening in children will depend on the earliest age of diagnosis/onset in the family.
First-degree relatives of anyone with a TAA need ongoing imaging surveillance, which typically consists of an echocardiogram (provided the region at-risk can be visualized by echocardiogram), which, if normal, should be repeated every 5 years until at least 65 years of age.
Fluoroquinolones should be avoided as much as possible in anyone with aortic aneurysms or at risk for aortic aneurysm (thoracic or not, hereditary or not), because of the associated increased risk of aortic dissection.
Download the PDF here. Click here to view the concise GECKO on the run or the point of care tool.
Bottom line:Hereditary thoracic aortic disease (HTAD) accounts for 20-25% of thoracic aortic aneurysms and dissections. Most individuals with HTAD do not have additional associated features (non-syndromic). HTAD presents at a younger age and is more aggressive than other thoracic aortic aneurysms (TAA). Appropriate recognition of HTAD allows initiation of imaging surveillance in at-risk relatives. Genetic testing should be offered to individuals with TAA who have at least one of the following red flags:
Thoracic aortic dilation reported on imaging as mild or greater, at age <50y or <60y in the absence of hypertension
Thoracic aortic dissection at age <60y or <70y in the absence of hypertension
Positive family history
Pathogenic variant in a HTAD gene identified in a relative
Syndromic features e.g. features of Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos Syndrome (EDS)
Identification of a genetic etiology can help guide pharmacotherapy, determine vascular regions which require ongoing imaging surveillance, and influence surgical thresholds as these are lower for HTAD versus degenerative type aneurysms.
An uninformative (negative) genetic test result does not exclude HTAD and at-risk relatives would still need ongoing imaging surveillance.
Pharmacological management for those with TAA may include:
beta-blockers or angiotensin receptor blockers to limit aneurysmal dilation.
avoidance of medications and recreational drugs with potential vasoactive effect (e.g. triptans, cocaine).
Fluoroquinolones should be avoided where possible in anyone with or at risk for aortic aneurysms of any type because of the associated increased risk of aortic dissection.
Participation in competitive sports and isometric exercises are advised against.
Key definitions
Dilation: when the diameter of the aorta exceeds the norms for a given age and body size. Reported as borderline, mild, moderate or severe on imaging.
Aneurysm: a dilation >50% larger than the blood vessel should be. All aneurysms are dilations, however not every dilation will reach the size of an aneurysm.
Dissection: a rip or tear in the inner lining of a blood vessel.
Degenerative: an aneurysm caused by the deterioration of a blood vessel over time, associated with risk factors such as high blood pressure, age, and smoking.
What is hereditary thoracic aortic disease (HTAD)?
Approximately 75% of thoracic aortic aneurysms (TAA) do not have a strong hereditary component. Most are degenerative and are primarily caused by age and hypertension. TAA may also have infectious/inflammatory and traumatic etiologies.
Approximately 25% of TAA are hereditary. About 20% of individuals with a TAA have no additional associated features (non-syndromic) but do have a positive family history. Five percent of individuals with TAA will have a syndromic condition (e.g. Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos Syndrome (EDS)). These persons may be the first individual with this condition (de novo) in their family.
Individuals with HTAD typically present at a younger age and have more aggressive disease than individuals with degenerative TAA. However, the age of onset, even within members of the same family, can be variable. Both those assigned male and those assigned female at birth can be affected. Certain co-morbidities are more common in patients with HTAD. These include migraine headaches, sleep apnea, and joint hypermobility.
TAA are typically asymptomatic but can lead to aortic dissections. Emergency aortic repair is associated with a 50% mortality. Individuals diagnosed with a TAA prior to dissection can benefit from pharmacotherapy, lifestyle modification and, if required, elective surgical repair (associated with a 1-2% mortality rate).
Imaging is required for diagnosis of a TAA. Interpretation of the dimensions of the aortic root should take into account age, sex, height and weight. Echocardiogram assesses the aortic root and the proximal portion of the ascending aorta. CT-angiogram and MR-angiogram of the chest assess the entire thoracic aorta. In order to assess the aortic root accurately, images need to be cardiac-gated (synchronized with heartbeat to control for motion artifacts). The choice of imaging modality will depend on the arterial region at risk. In individuals with a confirmed diagnosis of TAA, a combination of echocardiogram and CT/MRI is often used, with surgical decisions being based on CT/MRI data.
What do I need to know about the genetics of HTAD?
In most families, HTAD is inherited in an autosomal dominant fashion, which means first degree relatives of an affected individual are at 50% risk. Multiple genes are associated with HTAD. Current genetic testing for HTAD only identifies about 20% of disease-causing gene variants. Most individuals will receive a negative genetic test result, but this does not rule out an inherited condition. Genetic testing is always initiated in an affected individual in the family, the person most likely to have the inherited condition.
How common is HTAD?
The prevalence of TAA is approximately 6-10 individuals per 100,000, which means that 1-2 people per 100,000 have the inherited type [HTAD]. This is likely an underestimate as a thoracic aortic dissection presents remarkably similarly to a myocardial infarction and can be missed.
Who to consider referring for a genetic assessment?
Consider referral for a genetic assessment for individuals with a:
Thoracic aortic dilation reported on imaging as mild or greater, at age <50y or <60y in the absence of hypertension
Thoracic aortic dissection at age <60y or <70y in the absence of hypertension
Thoracic aortic dilation reported on imaging as mild or greater, at any age in the presence of any of the following family histories in a 1st or 2nd degree relative:
TAA or thoracic aortic dissection
Sudden cardiac death at age <50y without a confirmed alternate etiology
Personal or family history of thoracic aortic dilation or TAA at any age, and features that suggest an underlying syndromic condition, such as:
Tall for family (or tall and from a family where individuals with aneurysms tend to be significantly taller than those without aneurysms)
Ectopia lentis (lens dislocation)
Spontaneous pneumothorax (particularly if recurrent)
Hypertelorism (wide-spaced eyes)
Bifid uvula
Hollow organ rupture e.g. uterus, colon
Spontaneous tendon rupture
Large and unprovoked bruising (prior to anti-coagulation)
Very translucent skin
Pectus carinatum or significant pectus excavatum
Scoliosis requiring bracing or surgery
Significant varicose veins at a young age
1st or 2nd degree relative in whom a pathogenic variant in one of the hereditary thoracic aortic disease (HTAD) genes has been identified (referral of 3rd degree relatives can be considered when intervening relatives are not available for or decline testing)
Currently the decision to offer genetic testing is made in the setting of a genetics and/or cardiology consult. Click here to connect to your local genetics centre. Most genetic testing for HTAD is panel-based, where multiple genes are tested concurrently.
Information which should be included with your referral:
Recent echocardiogram report
Results of genetic testing/copy of the genetic testing report in family members if applicable
If available:
other imaging results (CT/MRI)
copy of any relevant consultations (ophthalmology, etc.)
Note that cardiogenetics/general genetics centres vary with regard to the referrals they accept. You may want to contact your local genetics centre or aortopathy/cardiogenetics program for more information.
What does the genetic test result mean?
The detection rate of genetic testing for hereditary thoracic aortic disease (HTAD) is approximately 20%, which means that 80% of individuals with HTAD will not receive an informative (positive) result. Test results fall into three categories:
Positive: causative pathogenic variant detected in a HTAD gene
This confirms a genetic etiology and a diagnosis of HTAD.
These results can be used to guide management (e.g. pharmacotherapy such as beta-blocker blocker to limit aneurysmal dilation and avoidance of fluoroquinolones, determine vascular regions which require ongoing imaging surveillance and influence surgical threshold).
Genetic testing can be offered to relatives for the familial gene variant. Those identified to be at-risk can be referred to an aortic clinic (preferably) or to cardiology for assessment.
Negative
Uninformative: no causative pathogenic variant detected in any HTAD gene tested
A diagnosis of HTAD is neither confirmed nor ruled out.
Genetic testing cannot be offered to unaffected relatives.
Over time, a better test may become available and re-referring to genetics can be considered in approximately 5 years.
True negative: the familial pathogenic variant is not detected
This is where genetic testing is offered to an unaffected relative after the causative pathogenic gene variant has been identified.
The individual does not have the familial condition and is not at increased risk to develop thoracic aortic aneurysms (TAA).
This individual’s offspring would not have increased risk for TAA.
Variant of unknown significance (VUS): variant in HTAD-related gene is detected, but there is insufficient evidence to determine if it is truly associated with disease. (It is possible for more than one VUS to be detected.)
Depending on the variant and gene, additional imaging might be recommended to better assess for other clinical manifestations.
The genetics team may offer testing to other relatives affected with TAA to see if the variant is present in those with disease and absent in unaffected relatives (segregation study).
Over time, additional information about the variant may become available and re-referring to genetics can be considered in approximately 5 years.
Genetic testing for hereditary thoracic aortic disease (HTAD) can help to:
Determine at what frequency imaging surveillance is needed and for which arterial beds.
Guide surgical threshold for aortic repair (recommendations for surgical thresholds vary depending on the underlying responsible gene).
Select the best medication for treatment.
Decide who in a family needs to continue to undergo imaging surveillance.
Assist with life planning (e.g., decisions about career, participation in competitive sports).
Provide relief to those who test negative for a known family variant.
Are there harms or limitations of genetic testing?
Current genetic testing for HTAD will only identify a causative pathogenic gene variant in about 20% of cases. Genetic testing can result in:
Adverse psychological reactions, particularly due to potential for risk of sudden cardiac death
Uncertainty due to a genetic variant of unknown significance
Surveillance and Management
Fluoroquinolones should be avoided as much as possible in anyone with aortic aneurysms or at risk for aortic aneurysm (thoracic or not, hereditary or not), because of the associated increased risk of aortic dissection.
For individuals with a thoracic aortic aneurysm (TAA):
Management in terms of frequency of imaging, pharmacotherapy, vascular regions requiring ongoing imaging surveillance and surgical threshold will be influenced by the underlying gene (and sometimes the underlying variant). Pharmacotherapy typically includes a beta-blocker or an angiotensin receptor blocker to limit aneurysmal dilation.
Individuals with TAA are usually advised against participation in competitive sports and told to avoid isometric exercises. Some medications and recreational drugs with a potent vasoactive effect (e.g. triptans, cocaine) are discouraged in individuals with TAA.
Individuals with HTAD should be referred to an aortic clinic (preferably) or to a cardiologist.
For individuals with a family history of HTAD:
Transthoracic echocardiography (TTE) is the primary imaging tool for screening of family members. CT or MRI at initial evaluation are also recommended to exclude the presence of aneurysms at areas poorly visualized by TTE. Family history (e.g. aneurysm outside thoracic aorta, intracranial aneurysm) may guide additional screening recommendations.
When a disease-causing variant is identified in a family member with TAA, at-risk relatives can be offered predictive genetic testing. The question of when to test children will depend on the specific gene.
All 1st degree relatives of an affected person should have regular surveillance unless they test negative for a known disease-causing familial genetic variant. The specific surveillance will depend on the underlying gene identified in the family. Individuals who test positive for the familial variant should be referred to an aortic clinic (preferably) or to cardiology and genetics.
Individuals who test positive for the familial variant and have not developed aortic dilatation typically do not have exercise restriction, but careful consideration should be paid before an at-risk individual constructs a life plan around activities (e.g. high-level competitive sports) which would become contra-indicated should they develop aortic dilatation.
When no disease-causing variant is identified in the family, first degree relatives of anyone in the family with a thoracic aortic aneurysm need ongoing imaging surveillance. Screening can start at age 25 years or 10 years earlier than the earliest diagnosis. The question of when to initiate screening in children will depend on the earliest age of diagnosis/onset in the family.
Surveillance typically consists of an echocardiogram (provided the region at-risk can be visualized by echocardiogram), which, if normal, should be repeated every 5 years until at least 65 years of age.
What about abdominal aortic aneurysm (AAA)?
AAA is more common in the general population and is much more strongly associated with traditional risk factors for coronary artery disease. AAA is less likely to be associated with a genetic predisposition than TAA, however, some conditions predisposing to HTAD can also predispose to AAA. In this context, aneurysms outside of the thoracic aorta are still considered pertinent if there is a family or personal history of TAA.
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References
Boodhwani et al. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol. 2014 Jun;30(6):577-89
McLure et al. The aortic team model and collaborative decision pathways for the management of complex aortic disease: Clinical practice update from the Canadian Cardiovascular Society/Canadian Society of Cardiac Surgeons/Canadian Society for Vascular Surgery/Canadian Association for Interventional Radiology. Canadian Journal of Cardiology Volume 39 2023
Isselbacher et al. 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: A report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022;146:e334–e482
Verhagen et al. Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives. Int J Cardiol. 2018 May 1;258:243-248
Rawla et al. Fluoroquinolones and the Risk of Aortic Aneurysm or Aortic Dissection: A Systematic Review and Meta-Analysis. Cardiovasc Hematol Agents Med Chem. 2019;17(1):3-10
Food and Drug Administration Drug Safety Communication. December 2018. FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics [Accessed Feb 2024]
Canadian Task Force on Preventive Health Care. Recommendations on screening for abdominal aortic aneurysm in primary care. CMAJ 2017;189(36):E1137-E1145 https://www.cmaj.ca/content/189/36/E1137
Author: J Richer MD FCCMG FRCPC
Edited by GECKO team: JC Carroll MD CCFP, JE Allanson MD FRCPC, S Walji MD CCFP MPH, S Morrison MS CGC
Point of care tool: 1-page, features a bottom line and criteria for genetic assessment. (March 2024)
GECKO on the run: A 2-page, evidence-based summary for healthcare practitioners. Features a bottom line, clinical features, criteria for genetic assessment, possible genetic results, surveillance and management,(March 2024)
GECKO deep dive: A 6-page, comprehensive evidence-based resource for healthcare practitioners. Features a bottom line, clinical features, criteria for genetic assessment, benefits and limitations of genetic testing and possible results, surveillance and management, references and more. (March 2024)
Bottom line:Familial hypercholesterolemia (FH) is a common (~1/250) autosomal dominant condition that results in a 6- to 22-fold increase in premature cardiovascular disease (CVD) and death. Early diagnosis and treatment can normalize life expectancy. Key features of FH are elevated LDL-C ≥5 mmol/L, early onset CVD (<55 years in men, <65 years in women), cholesterol deposition in the tendons (xanthomata) and/or around the eyes (xanthelasma), arcus cornealis with onset <45 years, and family history of early onset CVD or hyperlipidemia requiring treatment. In Canada, a diagnosis of FH is typically based on an individual’s clinical presentation and history as outlined in the Canadian Cardiovascular Society algorithm. Genetic testing is not widely clinically available in Canada with some exceptions. A clinical diagnosis guides treatment and screening of family members. Once a person is diagnosed with FH, cascade screening of family members using measurement of LDL-C levels and/or genetic testing is recommended. This enables early identification and treatment of at-risk individuals, with statins as first-line treatment.
What is familial hypercholesterolemia?
Familial hypercholesterolemia (FH) is an autosomal dominant genetic condition where the uptake of low-density lipoprotein cholesterol (LDL-C) into cells is either decreased or inhibited. This results in lifetime exposure to very high levels of LDL-C. FH is the most common genetic disorder causing premature cardiovascular disease (CVD) and death in both men and women. FH is both underdiagnosed and undertreated worldwide despite the knowledge that early diagnosis and treatment can normalize life expectancy.1-3 It is estimated that roughly 1 in 250 Canadians has FH, and that only about 10% have been identified.1,4
What do I need to know about the genetics of familial hypercholesterolemia?
Most cases (up to 80%) of familial hypercholesterolemia (FH) are caused by pathogenic/likely pathogenic (P/LP) variants (what used to be called mutations) in the LDL receptor gene LDLR, in which > 3000 different P/LP variants have been identified.2,5,6 The LDLR protein binds LDL, which is the major cholesterol-carrying lipoprotein of plasma, and transports LDL into cells by endocytosis. P/LP variants in the LDLR gene can reduce the number of LDL receptors produced within cells or disrupt the ability of the receptor to bind LDL particles.2 P/LP variants in APOB disrupt binding of LDL particles to the receptor, while P/LP variants in PCSK9 cause increased degradation of the receptor. These mechanisms lead to elevated LDL-C levels and premature development of atherosclerotic plaque.
Additional genes (e.g. ABCG5, ABCG8, APOE, LDLRAP1, LIPA) are known to be associated with FH, although very rare and atypical. With advances in genetic testing technology, additional rare genes can be added to gene panels with little extra cost. Genetic testing for FH may involve a gene panel with comprehensive analysis of three or more genes or may be targeted ancestry-based testing looking for the presence or absence of specific P/LP variants.7
Pattern of inheritance
FH is typically inherited in an autosomal dominant manner. FH can be present in a heterozygous form (HeFH), where only one copy of a FH-causing gene contains a P/LP variant. FH can also be present in a homozygous form (HoFH) where an individual has a P/LP variant in both copies of a FH-causing gene. The two P/LP variants can be identical or different. Rarely there is a P/LP variant in one copy of two different FH genes (digenic inheritance). All individuals with HoFH have an extremely high risk of early onset cardiovascular disease.1,3 If both parents have HeFH, their child has a 25% chance to have HoFH, which is associated with an extremely high CVD risk.
Table 1. Clinical features of familial hypercholesterolemia in heterozygotes (HeFH) and homozygotes (HoFH).
*The CardioRisk app has a validated algorithm to impute a baseline value from LDL-C levels while on lipid lowering medications, additionally it can be used for the clinical diagnosis of FH, assessing the degree of severity of FH for new patients and helps facilitate FH diagnosis.
How common is familial hypercholesterolemia?
About 1 in 250 Canadians is thought to have heterozygous familial hypercholesterolemia (HeFH), however FH is significantly under-recognized in Canada.1 Homozygous-FH (HoFH) is much rarer, and more severe and is expected to affect between 1 in 250,000 and 1 in 1,000,000 Canadians.8 FH is more common in certain populations due to founder effects: in certain areas of Quebec, the prevalence is as high as 1 in 80.9
How is familial hypercholesterolemia diagnosed?
The Canadian Cardiovascular Society (CCS) recommends the use of the Canadian diagnostic criteria for FH proposed by the Familial Hypercholesterolemia Canada (FHCanada) network (Figure 1).10 While these criteria are relatively new, they are less complicated than those published by the Dutch Lipid Clinic Network (DLCNC) (Table 2) or the Simon Broome Registry (Table 3) and have been validated against each of these criteria, which are internationally accepted for the diagnosis of HeFH.10 The Simon Broome Registry criteria include lower thresholds for children with suspected FH.11 Neither the DLCNC nor Simon Broome Registry criteria were designed to diagnose HoFH, for which other criteria have been suggested.8 The European Atherosclerosis Society has recently published clinical and genetic diagnostic criteria for HoFH.8 Genetic testing is not necessary for diagnosis and is not yet routinely clinically available in most of Canada. See the How to order the genetic testing for FH for more.
Figure 1. Canadian criteria for the clinical diagnosis of familial hypercholesterolemia (FH). From Ruel I et al, 201810. Reprinted with permission under the CC BY-NC-ND license https://creativecommons.org/licenses/by-nc-nd/4.0/. DOI: 10.1016/j.cjca.2018.05.015
ASCVD: atherosclerotic cardiovascular disease; LDL-C: low-density lipoprotein cholesterol. * Secondary causes of high LDL-C should be ruled out (severe or untreated hypothyroidism, nephrotic syndrome, hepatic disease [biliary cirrhosis], medication, especially antiretroviral agents) ** DNA mutation refers to the presence of a known FH-causing variant in a FH gene in the individual or a first-degree relative. FH diagnosis in a patient with a P/LP variant but normal LDL-C levels is unclear. Yearly follow-up of the individual is suggested, and cascade screening of family members should be initiated.
Cascade screening for family members
The most cost-effective approach for identification of new FH cases is cascade screening of family members of the first individual with a confirmed diagnosis, known as the index case.4,11,13 Data from the UK have shown that cascade screening reduces the average age at which an individual is diagnosed and results in an increased number of individuals who are treated with statins and have subsequent lowered lipid levels.14
The Canadian Cardiovascular Society (CCS) recommends screening of first-degree relatives of the index case.1 Screening can include lipid profiles of relatives and/or genetic testing for a known familial P/LP variant, when available. Each newly diagnosed individual becomes a new index case and cascade screening of relatives continues.
When using a genetic testing approach, testing relatives for a known familial P/LP variant, positive results will identify at-risk relatives and negative results would reassure those at population risk. When ordering genetic testing for relatives it is important to include documentation of the familial genetic variant either with a molecular report or a family letter. This ensures accurate interpretation of testing.
How to order genetic testing for familial hypercholesterolemia?
Genetic testing is not necessary for diagnosis and is not yet routinely clinically available in most of Canada. See the links below to where testing is clinically available and the testing criteria.
Genetic testing in Québec (Feb 2023)
The Core Molecular Diagnostic Laboratory at the McGill University Health Centre
CHU Sainte Justine Molecular Laboratory
Genetic testing in Ontario (as of January 2024) can be ordered by any physician and does not require a referral for genetic assessment. Testing criteria are on each requisition and can be found on the Ontario Provincial Genetics Program site..
London Health Sciences Centre (LHSC Requisition) molecular laboratory
Trillium Health Partners – Credit Valley Site (THP Requisition)
Hamilton Regional Laboratory Medicine Program (Requisition)
Other provinces are looking at how to implement genetic testing and screening.
Quebec Requisitions
Ontario Requisitions
The Core Molecular Diagnostic Laboratory at the McGill University Health Centre
CHU Sainte Justine Molecular Laboratory
London Health Sciences Centre (LHSC Requisition) molecular laboratory
Trillium Health Partners – Credit Valley Site (THP Requisition)
Hamilton Regional Laboratory Medicine Program (Requisition)
Positive: causative pathogenic variant detected in an FH gene
This confirms a genetic etiology and a diagnosis of FH.
These results can be used to guide management.
Genetic testing can be offered to relatives for the familial gene variant.
Negative
Uninformative: no causative pathogenic variant detected in any FH gene tested
A diagnosis of FH is neither confirmed nor ruled out.
If testing was limited to ancestry-based screening (where only select genetic variants in select genes were analysed), expanded testing may be considered, if available.
Genetic testing cannot be offered to unaffected relatives. Lipid screening can be used for at-risk relatives.
Re-referring to genetics can be considered if/when genetic testing improves.
True negative: the familial P/LP variant is not detected
This is where genetic testing is offered to an unaffected relative after the causative pathogenic gene variant has been identified.
The individual does not have the familial condition and is not at increased risk for dyslipidemia.
This individual’s offspring would also not have increased risk for dyslipidemia.
Variant of unknown significance: variant in FH-related gene is detected, but there is insufficient evidence to determine if it is truly associated with disease
A diagnosis of FH is neither confirmed nor ruled out.
Genetic testing is not offered to unaffected relatives. Lipid screening can be used for at-risk relatives.
Segregation studies may be considered. This is where genetic testing is offered to other affected relatives to try and track if the VUS is present in others with the condition.
Re-referring to genetics can be considered as over time a VUS may be reclassified as benign or pathogenic.
What are the benefits and considerations of genetic testing for familial hypercholesterolemia?
Benefits
Confirmation of diagnosis:15Genetic testing is a key approach to the diagnosis of definite FH. While clinical criteria can be used (Table 2 and 3) for diagnosis, there are limitations to using the classical presentation as a criterion since few affected persons will exhibit physical findings (e.g. xanthomas, xanthelasmas) at the time of testing. Additionally, there are limitations to use of family history of cardiovascular disease in FH diagnosis. Hypercholesterolemia or heart disease could be masked in relatives who are receiving lipid lowering treatment. Also, the penetrance of FH is very strong but not complete (i.e. not all variant carriers will develop hypercholesterolemia), and self-reported family history is not always accurate. Screening for FH based on family history alone has shown to miss 30-60% of cases.16
Refining risk stratification:15Detection of a pathogenic variant in an FH gene indicates higher cardiovascular risk (compared to those at the same LDL-C levels) and the need for more aggressive LDL-C reduction. The use of conventional cardiovascular risk calculators in individuals with FH is not recommended as these greatly underestimate lifetime CVD risk.1,2, 17
Value to children and adolescence:15Statin treatment in children identified as carrying a pathogenic variant in an FH gene may begin as young as 8 years of age. Children with FH who start a statin have statistically lower event rates than their affected parents. Left untreated, children with FH will be at higher risk of coronary events as adults because of the cumulative burden of elevated LDL-C levels.
Considerations
Sensitivity: Current genetic testing does not detect all possible genetic causes of FH and so a negative test result would not rule out an FH diagnosis.
Accessibility: Genetic testing for FH is not equitably available across Canada. Some provinces (Ontario, Quebec) offer testing through provincial laboratories. Other locations do not have in-province access. It may be possible to request funding for out-of-country testing or through research avenues.
Surveillance and Management
Adults
For more on the management and screening of dyslipidemia in adults, please see the 2021 guidelines from the Canadian Cardiovascular Society (CCS).17 These recommendations include universal lipid screening of men and women at average risk age 40 years and older, or earlier screening for those at increased risk for CVD. CCS also recommends regular atherosclerotic cardiovascular disease (ASCVD) risk assessments every 5 years for men and women aged 40-75 years, using a validated risk model (e.g. Framingham Risk Score [FRS] or the Cardiovascular Life Expectancy Model [CLEM]). Recent PEER simplified guidelines18 suggest for those at average risk of CVD, universal lipid screening at starting age 40 for those assigned male at birth and at age 50 for those assigned female at birth. If CVD risk factors are present, screening can be considered younger.
The use of conventional cardiovascular risk calculators in individuals with FH is not recommended as these greatly underestimate lifetime CVD risk.1,2, 19 FH-specific cardiovascular risk calculators (e.g. the FH Risk Score20, SAFEHEART 19) should be considered to assess the risk of ASCVD in those with FH. Routine assessment and stratification of the risk of ASCVD in all patients with FH should be used to guide personalized treatment and management.19 Referral to specialist for risk stratification is recommended.
Those with homozygous status (HoFH, two pathogenic/likely pathogenic (P/LP) variants in an FH gene) should be referred to a specialized lipid centre.1
A genetic diagnosis of FH in a person with a P/LP variant but normal LDL-C levels is unclear. Yearly follow-up of the individual is suggested, and cascade screening of family members should be initiated.1
Pharmaceuticals
Statins are the drug class of choice for individuals with one P/LP variant in a FH gene (HeFH). Observational studies have shown a dramatic decrease in cardiac events in statin-treated individuals with FH.1 LDL-C should be lowered as fast and as far as possible.3The CCS recommends a >50% reduction of LDL-C from baseline beginning at age 18 as primary prevention and that an ideal goal of LDL-C <1.8 mmol/L is recommended for secondary prevention.17 Non-fasting lipid profiles should be used to monitor treatment in those whose treatment is stable.20 The use of high-dose statins alone is usually sufficient to achieve LDL-C reduction; however, some individuals with FH will require combination (e.g. ezetimibe) and/or emerging therapy (e.g. PCKS9 inhibitor) to obtain optimal LDL-C. Specialist referral referral is recommended for these cases.1-3,17,23
For the most recent recommendations on management and treatment of individuals with HoFH please see Cuchel et al. 2023.8
Lifestyle
All families with FH (including children and adolescents) should be counselled about the importance of lifestyle modification and heart healthy behaviour1-3,17,19 such as:
Smoking cessation and avoidance of passive smoking
Diet
High in fibre (soluble), plant sterols/stanols and unsaturated fatty acids
Low in trans and saturated fatty acids, refined sugars
Exercise
Daily activity beginning early in life
Maintenance of ideal body weight
Stress reduction
Pregnancy
Statins have been considered a teratogen on the basis of animal studies, however human studies have shown conflicting results.20 For most persons assigned female at birth who are of reproductive age, an effective birth control method is recommended with discontinuation of statin therapy ideally 3 months prior to planned pregnancy or at the time of a positive pregnancy test.1,20,21 Bile acid sequestrants can be considered to treat hypercholesterolemia, ideally 3 months before a planned pregnancy, as well as during pregnancy and lactation.19 The CCS recommends referral to a maternal-fetal-medicine or obstetrical specialist for management of lipid reducing therapies.17 A pregnant person with FH and additional risk factors, e.g. established ASCVD, should be referred to a speciality lipid clinic for further treatment advice.
Children /Adolescents
There remains controversy as to whether screening in childhood for FH should be implemented.1 A recent systematic review by the US Preventive Services Task Force found that the use of statins in children to reduce lipid levels appears beneficial, and observational studies show there is long-term benefit.20 The CCS and Canadian Pediatric Cardiology Association recommend universal lipid screening (fasting or non-fasting, non-HDL-C or LDL-C) be performed after 2 years of age within the first decade of life.21 Selective screening at anytime can be considered when there is a positive family history of premature CVD or dyslipidemia, or other cardiovascular risk factors.21 Reverse cascade screening of parents is recommended when a child is found to have FH.1,21
The ideal age to begin treatment is between ages 8-12 years based on current randomized control trials.21 Pharmacological treatment can be considered, incorporating clinical judgement, family and patient preferences,1,19,21 at:
Age 8-10 years when LDL-C concentration >4.9 mmol/l, recorded on two occasions with a fasting lipid profile.
Age 8–10 years when LDL-C concentration >4.0 mmol/l, recorded on two occasions with a fasting lipid profile, in the presence of multiple ASCVD risk factors or family history of premature ASCVD.
Age <8 years with an LDL-C concentration >4.9 mmol/l, recorded on two occasions.
The use of treatment in this group does require specialist input as further study regarding the use is still needed.21
An LDL-C goal of <3.5 mmol/l or approximately 50% reduction may be considered in children/adolescents with no additional risk factors for ASCVD (e.g. diabetes, parental history of ASCVD in the second or third decade of life). Yearly non-fasting LDL-C levels in blood can be used to monitor those who have met LDL-C goal after initiation and titration of therapy, with no further dose change.19 Canadian Lipid Guidelines17 indicate LDL-C and non-HDL-C are interchangeable but non-HDL-C is preferable for non-fasting samples and if triglycerides > 1.5 mmol/L.
Lifestyle modifications discussed above remain the cornerstone of CVD prevention in both children and adolescents with FH and referral to a specialist to a specialist for treatment decisions is recommended.1The CCS recommends that children with HoFH are referred to a lipid specialist centre for cholesterol-lowering therapies when >15kg in weight.
Additional guidance on management of dyslipidemia in children and adolescence can be found here.21
Other provinces are looking at how to implement genetic testing and screening.
References
[1] Brunham LR, Ruel I, Aljenedil S, Rivière J, Baass A, Tu JV, et al. Canadian Cardiovascular Society position statement on familial hypercholesterolemia: Update 2018. Can J Cardiol. 2018. 34(12):1553-1563.
[3] Vogt A. The genetics of familial hypercholesterolemia and emerging therapies. Appl Clin Genet. 2015. 8: 27-36.
[4] Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, Chu A, Tu JV. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. BMJ Open 2017;7(9)e016461.
[5] Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013. 34(45): 3478-3490a.
[6] Hartgers ML, Ray KK, Hovingh GK. New approaches in detection and treatment of familial hypercholesterolemia. Curr Cardio Rep. 2015. 17: 109.
[7] Hegele RA, Ban MR, Cao H, et al. Targeted next-generation sequencing in monogenic dyslipidemias. Curr Opin Lipidol. 2015; 26(2):103-13.
[8] Cuchel M, Raal FJ, Hegele RA, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023 Jul 1;44(25):2277-2291.
[9] Brunham L, Ruel I, Khoury E, Hegele RA, Couture P, Bergeron J, et al. Familial hypercholesterolemia in Canada: initial results from the FH Canada National Registry. Atherosclerosis. 2018. 277: 419-424.
[10] Ruel I, Brisson D, Aljenedil S, Awan Z, Baass A, Bélanger A, et al. Simplified Canadian definition for familial hypercholesterolemia. Can J Cardiol. 2018. 34: 1210-1214.
[11] Turgeon RD, Barry AR, Pearson GJ. Familial hypercholesterolemia: review of diagnosis, screening, and treatment. Can Fam Physician. 2016. 62(1): 32-37.
[12] Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004.160(5): 407-420.
[13] Knowles JW, Rader DJ, Khoury MJ. Cascade screening for familial hypercholesterolemia and the use of genetic testing. JAMA. 318(4): 381-382.
[14] Ned RM, Sijbrands EJ. Cascade screening for familial hypercholesterolemia (FH). PLoS Curr. 2011. 3: RRN1238.
[15] Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel. J Am Coll Cardiol. 2018 Aug 7;72(6):662-680.
[16] Khoury M. Cascade screening in familial hypercholesterolemia: achieving buy-in and turning patients into partners. CJC Pediatr Congenit Heart Dis. 2023 Jun 20;2(5):219-221.
[17] Pearson GJ, Thanassoulis G, Anderson TJ, et al. 2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol. 2021 Aug;37(8):1129-1150. doi: 10.1016/j.cjca.2021.03.016. Epub 2021 Mar 26.
[18] Kolber MR, Klarenbach S, Cauchon M, et al. PEER simplified lipid guideline 2023 update: prevention and management of cardiovascular disease in primary care. Can Fam Physician. 2023 Oct;69(10):675-686.
[19] Watts GF, Gidding SS, Hegele RA, et al. International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia. Nat Rev Cardiol. 2023 Dec;20(12):845-869
[20] Paquette M, Bernard S, Cariou B, et al. A. Familial hypercholesterolemia-risk-score: a new score predicting cardiovascular events and cardiovascular mortality in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2021 Oct;41(10):2632-2640
[21] Guirguis-Blake JM, Evans CV, Coppola EL, et al. Screening for lipid disorders in children and adolescents: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2023 Jul 18;330(3):261-274.
Authors: S Morrison MS CGC, JE Allanson MD FRCPC, RA Hegele MD FRCPC, S Walji MD CCFP and JC Carroll MD CCFP
GECKO Deep Dive is for educational purposes only and should not be used as a substitute for clinical judgement. GECKO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgment in addition to published articles and the information presented herein. GECKO assumes no responsibility or liability resulting from the use of information contained herein.
Prenatal Screening is an option available to everyone during pregnancy. You can decide whether or not you would like to have prenatal screening. The guide is meant to help people decide whether or not prenatal screening is right for them.
In Canada, about 1 in 25 (4%) babies is born with a difference or variation, called a congenital anomaly, which may require medical or surgical intervention. The most common variations are structural heart defects, cleft lip and/or palate or a pattern of variations such as Down syndrome. Some risk factors, like family history or the pregnant person/egg donor’s age, can increase the chance that a person will have a baby with an anomaly. If you have any concerns about your family history, for example you have a genetic condition, there are close relatives with intellectual disability or who were born with one or more anomalies, young children or babies that passed away unexpectedly, be sure to discuss that with your health care practitioner.
Through available prenatal screening and detailed second trimester ultrasound, the chance to have a baby with some specific genetic conditions and anomalies can be more precisely determined. Prenatal screening is about risk assessment
What are prenatal screening tests?
Prenatal screening is available to people expecting a baby.
Test options vary in each region.
These are blood tests, sometimes accompanied by an ultrasound, that are performed early in pregnancy.
Prenatal screening determines your chance of having a baby with Down syndrome, trisomy 18 or an open neural tube defect. Prenatal screening can sometimes determine the chance of other genetic conditions and anomalies.
Many people expecting a baby have a difficult time deciding whether or not to have a prenatal screening test. Some people find it helpful to read this entire guide first, before making a decision.
The conditions for which prenatal screening is used
Down syndrome
People with Down syndrome are individuals who are just as unique and highly variable as anyone else. An individual with Down syndrome has an extra copy of chromosome 21 (trisomy 21). This usually causes mild to moderate intellectual disability, which means that adults will typically function at the level of an 8-10 year old. An individual with Down syndrome is expected to learn to read and write and to be physically active, however major developmental milestones will be delayed. Individuals with Down syndrome have a greater possibility of health conditions than the average person, such as heart, stomach, bowel, thyroid, vision and hearing problems. Treatment is available for many of these conditions. There is no way to predict how serious or mild these differences will be. The average life expectancy for a person with Down syndrome is now about 60 years old. In general, about one in 1000 babies born has Down syndrome. The chance of having a child with Down syndrome increases with the pregnant person/egg donor’s (in the case of a donated egg) age (See Table 3 in Additional Resources). For more information on Down syndrome, visit the Canadian Down Syndrome Society website.
Down syndrome
Babies with trisomy 18 have an extra chromosome 18. Every individual with trisomy 18 is different, however serious intellectual disabilities and congenital anomalies that may affect many organ systems (e.g. heart, kidneys) are expected. Many pregnancies with trisomy 18 will miscarry. Most babies born with trisomy 18 do not survive past the first few months of life. About 10% of infants will survive up to 5 years of age, or occasionally longer. Long-term survivors are described as socially interactive with significant physical and intellectual disabilities (e.g. having few words). In general, about one in 6,000 babies born has trisomy 18. The chance of having a child with trisomy 18 increases with the pregnant person/egg donor’s age. For more on trisomy 18, visit The Trisomy 18 Foundation website.
Open Neural Tube Defects
The neural tube is a structure in the early development of the central nervous system (the spinal cord and the brain). This structure is completely formed by about 6 weeks of pregnancy. Incomplete or failed formation of the neural tube leads to congenital anomalies of the brain or spinal cord and nerves. The effects of a neural tube defect are extremely varied and depend on the location and size of the defect. Open neural tube defects are the most common and serious. The neural tube defect is closed if the defect is covered by skin and the neural tissue is not exposed to amniotic fluid. A neural tube defect involving the spinal cord is called spina bifida. Spina bifida causes physical disabilities such as difficulty walking, and controlling the bladder and/or bowel. People with spina bifida may also have intellectual disabilities. Treatment can help with many of the physical disabilities. A neural tube defect involving the brain is called anencephaly. A baby with anencephaly will be stillborn or die shortly after birth. In Canada, the chance of having a baby with an open neural tube defect is about one in 1000 live births. The chance does not increase with the pregnant person/egg donor’s age. The chance does decrease when a prenatal vitamin with folic acid is taken. For more on spina bifida, see the Spina Bifida & Hydrocephalus Association of Ontario website. Talk to your health care provider about folic acid and prenatal vitamins.
Additional conditions which may be screened for by prenatal screening:
Trisomy 13 (Patau syndrome)
Babies with trisomy 13 have an extra chromosome 13. In general between 1/8,000 and 1/15,000 of babies born has trisomy 13. The chance of having a child with trisomy 13 increases with a pregnant person/egg donor’s age. Every individual with trisomy 13 is different; however each individual is expected to have both serious intellectual disabilities and congenital anomalies, including differences of the brain, heart, eyes and face. Most pregnancies with trisomy 13 will miscarry. About 5-10% of infants will survive the first year of life. There are some individuals who have lived to adulthood. For information on trisomy 13, visit Support Organization for Trisomy 18, 13 and Related Disorders (SOFT) website www.trisomy.org. See Additional Resources for more information about genetics.
Sex chromosome differences
Typically, each mature human cell contains 23 chromosome pairs (46 chromosomes in total). One of these chromosome pairs, the 23rd pair, is the sex chromosomes. A female cell will usually have two X chromosomes and a male cell will have one X chromosome and one Y chromosome. Some prenatal screening and diagnostic testing can identify extra or missing X and/or Y chromosomes. There are several conditions with sex chromosome differences. Generally, these types of genetic differences are quite common occurring in about 1 in 500 individuals. Expected features are variable and depend on which chromosome is extra or missing. Some features maybe as mild as tall or short size. There may be differences in development such as delayed speech or learning differences. There may be associated health issues involving puberty or the heart. Visit The Association for X and Y Chromosome Variations (AXYS) or the Turner Syndrome Society of Canada for more.
Remember…
You might decide to have prenatal screening because you want to know the chance that your baby has one of the conditions previously described. Prenatal screening uses the age of the pregnant person/egg donor, blood test(s) and/or ultrasound of the baby to determine a more accurate chance.
Are prenatal screening tests right for me?
It is your choice whether or not to have a prenatal screening test. There is not a right or wrong choice.
To help your decision-making, here are some questions people may ask themselves and discuss with a partner, health care practitioner, spiritual leader, family or friends.
Do I want to know the chance of my baby having Down syndrome, trisomy 18 or open neural tube defect?
What would I do with this information?
Consider…
What could you do with this information:
Pregnancy management: If you are found to be at increased risk for one of these conditions, your health care practitioner may suggest additional tests (e.g. diagnostic testing, more ultrasounds) and/or suggest changes to how your pregnancy is managed or the way your baby is delivered.
Reproductive choice: If I have a child with intellectual and/or physical disabilities, how might this affect my life, my other children, and my relationship with my partner and my extended family? Some people expecting a baby have screening because they would like the information before birth to help with decision-making in the pregnancy. If their baby was found to have one of these conditions they would:
prepare for a child with special needs (See point 5 for more)
consider giving the baby up for adoption
consider ending the pregnancy
Some people expecting a baby choose to not have screening because they would not:
have a diagnostic test under any circumstance because of the small risk of miscarriage
change the course of their pregnancy by choosing to end the pregnancy
Remember that most babies are born without an anomaly, however 1 in 25 babies in Canada is born with a difference at birth requiring medical intervention (congenital anomaly). Prenatal screening does not screen for all possible anomalies. There is no cure for Down syndrome, trisomy 18 or open neural tube defect.
How will this information affect my feelings throughout the pregnancy?
A low risk (screen negative) result is the most common outcome and those expectant individuals are likely to feel reassured
Consider…
how would I feel if I received an increased chance (screen positive) for one of these conditions? Many people expecting a baby experience anxiety and worry when their test results say that the chance of having a baby with one of these conditions is higher than expected.
If your screening test result says there is an increased chance (screen positive) your baby has Down syndrome, trisomy 18 or open neural tube defect, you will need to decide if you want diagnostic testing. A screening test can only tell you the chance (probability) that your baby has one of these conditions. A diagnostic test can tell you for sure whether or not your baby does have the condition. Prenatal diagnostic testing for Down syndrome or trisomy 18 consists of amniocentesis or chorionic villus sampling (CVS). In the case of open neural tube defects, diagnostic testing will include a detailed ultrasound, amniocentesis or other investigation.
Would I pursue diagnostic testing in the event of a screen positive result?
Consider…
Diagnostic testing will tell you if your baby has or does not have one of these conditions, but with amniocentesis and chorionic villus sampling (CVS) procedures there is a small chance of miscarriage (less than 1%).
Would I be willing to take that risk to have this information?
Diagnostic testing can also detect conditions for which you were not known to be at increased risk, such as another chromosome difference.
Would I want this additional information about my baby?
If Diagnostic testing confirms a baby has the condition, people expecting a baby need to decide if they want to continue the pregnancy or if they will end the pregnancy.
If more testing shows that my baby has a condition for sure, what will I do with the information? (See points 1, 2 and 5 for more)
5. If you know that you would not end a pregnancy for any reason, prenatal screening may still be an option for you. With a prenatal diagnosis you can: plan for the birth of your child; find out from others what it is like to raise a child with this condition; learn about resources available in your community; meet with various health care teams who may be involved with your child’s care; or look into adoption.
Consider…
Before the baby is born, to know for sure if a baby has one of these conditions, a diagnostic test like amniocentesis or chorionic villus sampling (CVS) is needed. Remember diagnostic tests are invasive and have a small chance of causing miscarriage
Diagnostic testing for a chromosome difference can be performed on a blood sample once a baby is born. This is a non-invasive option for people expecting a baby who would not change the course of their pregnancy based on such a diagnosis
Would this information be helpful to me before the birth or can I wait until my baby is born?
I have decided…
A. I do not want to have prenatal screening, now what?
Your health care practitioner will follow you as in any other pregnancy and make sure that both you and your baby are in the best possible health. Where available, you may be offered an ultrasound in the late first trimester (around 11-14 weeks gestation) for more accurate dating of your pregnancy, determination of twins, and early detection of major congenital anomalies. You may be offered an ultrasound in the second trimester at around 18 20 weeks gestation to look at the baby’s growth and anatomy.
B. I do not want to have prenatal screening but rather diagnostic testing, now what?
Your access to diagnostic testing will vary depending on where you live. If you, or in the case of a donor, the egg, will be 40 years or older at the time of birth you will likely have the option to choose diagnostic testing without prenatal screening. Talk to your health care practitioner about next steps. See diagnostic testing for more, and for more on available genetic tests see Additional Resources.
C. I do want to have prenatal screening, now what?
Once you have decided to proceed with prenatal screening, the next step is for you and your health care practitioner to choose which testing option is right for you. The following two tables compare available screening tests. Some factors that affect which prenatal screening tests you can choose from are:
— Where you live
Screening choices vary according to where you live. Your health care practitioner will discuss what is available.
— How far along you are in the pregnancy
Accurate dating of your pregnancy, determined by a first trimester ultrasound, is important for accurate screening results. Dating based on last menstrual period (LMP) is not ideal, but if a first trimester ultrasound is not available this dating can be used.
If the first prenatal visit with your health care practitioner is before 14 weeks (3 1/2 months) of pregnancy, options that may be presented to you include:
Enhanced First Trimester Screening (eFTS) and/or Non-Invasive Prenatal Testing (NIPT)
If the first prenatal visit with your health care practitioner is after 14 weeks (3-1/2 months) and before 21 weeks (~5 months) of pregnancy, options that may be presented to you include:
— The age of the pregnant person (or the egg in the case of a donated egg) when the baby is born
If the pregnant person will be 40 years of age or older at the time of birth, prenatal testing options include all screening tests above, possibly, in addition to the option of diagnostic testing.
If the pregnant person/egg donor will be 39 years of age or younger at the time of birth, prenatal options include all of the screening tests above, however NIPT would have to be paid for out of pocket and is not covered by Ontario Health Insurance Plan (OHIP). Diagnostic testing would not typically be offered at this time.
— Whether or not twins or higher order multiples (e.g. triplets) are present
Not all screening tests perform well when there is more than one baby
Non-Invasive Prenatal Testing (NIPT) and/or diagnostic testing may be offered
Nuchal translucency
In addition to blood work, many screening tests also include an ultrasound measurement called the nuchal translucency (NT). What is the NT measurement?
— The NT is a fluid filled space at the back of every baby’s neck (see image left)
— A larger NT measurement is associated with an increased chance for chromosome conditions like Down syndrome and some other genetic and non-genetic issues like congenital heart defect
— An ultrasound to measure NT is performed between 11 and 14 weeks of pregnancy and should be done at a certified ultrasound site. Your health care practitioner will tell you where an NT ultrasound can be obtained.
— An NT measurement of 3.5mm or bigger is considered significant and would be a screen positive. A referral for genetic counselling will likely be offered.
Table 1 has an overview of the prenatal screening tests available in Ontario and how they compare to each other. Not all test options are available in all areas.
Enhanced First Trimester Screening (eFTS) is the most commonly offered prenatal screening test. It screens for Down syndrome and trisomy 18. Results from eFTS are available early in pregnancy, allowing people time for decision making and access to additional services.
A person who presents to their first prenatal visit at a later gestational age (after 14 weeks) may be offered Multiple Marker Screening (MMS).
An ultrasound is recommended for all pregnant individuals at about 18 20 weeks of pregnancy to look at the baby’s growth and anatomy, regardless of prenatal screening results. While most babies are born without anomalies, 1 in 25 babies in Canada will be born with a difference that may require medical intervention. It is important to remember that no test can detect every type of anomaly.
If you are expecting twins, prenatal screening is available but in general is not as accurate as for pregnancies with one baby. Also, not all screening options will be available for a twin pregnancy. Talk to your health care provider for more about screening in a twin pregnancy.
Remember…
Your health care practitioner will help you choose the right prenatal screening test for you. Factors that affect what is available are: where you live, gestational age of the pregnancy at the time of the first prenatal visit, pregnant person/egg donor’s age at the time of birth, whether one or more babies are present.
The nuchal translucency (NT) can only be measured between 11 and 14 weeks of pregnancy at a certified ultrasound centre. This is a normal fluid filled space in every baby. You will likely be offered a referral to your local genetics centre if the NT measurement is greater than 3.5mm.
Table 1. Prenatal screening tests available and how they compare.
Components of test All screens use the pregnant person/egg donor’s age in risk assessments u/s = ultrasound NT = nuchal translucency
One blood test for pregnancy related hormones
u/s for NT
One blood test for cell-free (cf) DNA
One blood test for 3-4 pregnancy related hormones
Gestational age at first trimester blood test
11 – 13 weeks + 6 days
Recommended after 10 weeks
Not applicable
Gestational age at the NT ultrasound
11 – 13 weeks + 6 days
Not applicable
Not applicable
Gestational age at second trimester blood test
Not applicable
Not applicable
15 – 20 weeks + 6 days
Detection rate (these are approximate and depend upon the actual test/laboratory)
Meaning, how many pregnancies where the baby really does have Down syndrome will be flagged as increased risk this test?
85-90%
99%
80%
False positive rate (these are approximate and depend upon the actual test/laboratory)
Meaning, how many pregnancies will this test flag as increased risk BUT the baby does NOT really have Down syndrome?
About 3-6%
Less than 0.1%
About 5%
Conditions screened for
Down syndrome
Trisomy 18
Down syndrome
Trisomy 18
Trisomy 13
Sex chromosome differences
Down syndrome
Trisomy 18
Open neural tube defects
Non invasive prenatal testing by cell-free DNA: the latest in prenatal screening
What is non-invasive prenatal testing by cell-free DNA?
Non-Invasive Prenatal Testing (NIPT) is a screening test to estimate the chance that the unborn baby has Down syndrome or another chromosome condition (trisomy 18, trisomy 13 or an extra or missing sex chromosome). Normally genetic information (DNA) is contained within a cell (see the Additional Resources for an introduction to genetics). When a cell dies it releases its contents into the blood stream and the DNA is broken up into tiny pieces. This DNA is called cell-free DNA (cfDNA).
NIPT is also known as cfDNA screening. NIPT/cfDNA screening detects, reads and counts cfDNA in a pregnant person’s blood stream. Although this cfDNA is not directly from the baby, it is from the placenta and usually does represent the genetic profile of the baby.
What are the benefits of NIPT/cfDNA screening?
Accuracy: NIPT/cfDNA screening is more accurate than conventional prenatal screening tests, detecting more than 99% of pregnancies where the baby has Down syndrome (versus 75-90% by other screening methods). See Table 1 for more on conventional prenatal screening.
Fewer invasive (diagnostic) procedures: As the performance of NIPT/cfDNA is better than conventional prenatal screening, fewer pregnancies will be flagged as increased risk (screen positive) and go onto have diagnostic testing associated with small risk of miscarriage
Timing: The result from NIPT/cfDNA screening is available earlier than conventional prenatal screening. NIPT/cfDNA screening is just one blood test. Current Society of Obstetricians and Gynaecologists of Canada (SOGC) guidelines recommend that NIPT/cfDNA screening is performed after 10 weeks of gestation. Results are available about 1-2 weeks after testing. Having screening results earlier in pregnancy allows people expecting a baby more time for decision-making and potentially offers them more options.
Who should have NIPT/cfDNA screening?
NIPT/cfDNA screening is available to all pregnant people.
NIPT/cfDNA screening can be used as a second screen (i.e. after receiving a positive Enhanced First Trimester Screening result or if specific ultrasound differences have been found) or as a first screening test (e.g. before any other screening).
When there is an increased chance for a baby to have a chromosome condition, recommendations are that screening by NIPT/cfDNA be considered. In general, a pregnancy is considered to be at increased risk for a chromosome condition when:
The pregnant person is 40 years of age or older at the time of estimated date of birth
There are twins present
There is a screen positive result by conventional prenatal screening
NIPT/cfDNA screening could be used for sex determination
Who should have NIPT/cfDNA screening?
NIPT/cfDNA is typically offered by the most responsible prenatal care practitioner. This may be your family physician, nurse practitioner, obstetrician or genetic counsellor. NIPT/cfDNA is available in every province and territory. Public healthcare funding may be available if certain criteria are met. You can find links to your provincial prenatal screening program here and whether NIPT/cfDNA is funded in your area here.
Several companies offer NIPT/cfDNA through provincial programs and as private pay testing. The cost of NIPT/cfDNA varies but in general is about 100-400$. GECKO does not endorse one company over another. Your local genetics centre may provide information about the locally available test.
Several companies offer NIPT/cfDNA through provincial programs and as private pay testing. The cost of NIPT/cfDNA varies but in general is about 100-400$. GECKO does not endorse one company over another. Your local genetics centre may provide information about the locally available test.
Table 2 below has some information about NIPT/cfDNA testing companies available in Canada. The technology each company uses to calculate the risk of a chromosome condition is different, but the accuracy of the tests is comparable. If you choose to have NIPT/cfDNA, the company you and your health care practitioner choose may vary depending on factors listed in Table 2.
Table 2. Non-Invasive Prenatal Testing (NIPT) in Canada. Not every test is available everywhere.
What proportion of the pregnancies where the baby does have Down syndrome will be detected? (Detection rate)
>99%
>99%
>99% (as per company)
What proportion of the pregnancies where the baby does not have Down syndrome will be falsely called high risk? (False positive rate)
Less than 1 in 1,000 (0.1%)
Less than 1 in 1,000 (0.1%)
Is genetic counselling available through the company?+
Yes
Yes
Yes
Cost**
$495
$550
*The Society of Obstetricians and Gynaecologists of Canada guidelines recommend that NIPT/cfDNA screening is performed after 10 weeks of gestation because, prior to that time, there is an increased chance that the test will not give a result and will need to be repeated.
+Make sure the individual providing genetic counselling is a Canadian or American board-certified genetic counsellor to ensure that individual has met standards for providing competent genetic counselling care.
** Cost varies based on test options e.g. NIPT screening for chromosomal abnormalities alone or NIPT screening for chromosomal abnormalities and microdeletion syndromes.
Harmony and Panorama have agreements with the Ministry of Health and Long-term Care in Ontario [other provinces may have agreements as well]. They provide test performance data to the Better Outcomes Registry & Network allowing for quality assurance insight. Invitae does not and testing is performed outside of Canada.
What about the other genetic conditions screened for by NIPT/cfDNA screening?
You may have read that the NIPT/cfDNA screening can suggest other genetic conditions, such as microdeletion and microduplication syndromes. These are rare genetic conditions, occurring in about 1 in 5,000 to 1 in 50,000 pregnancies. They are caused by very tiny extra or missing pieces of chromosomes.
Most of these conditions occur by chance, meaning that they tend to not run in families and can occur out of the blue. The risk of these conditions is not associated with the pregnant person/egg donor’s age, as it is for Down syndrome and trisomy 18 (conditions caused by extra whole chromosomes).
The addition of these rare conditions to NIPT/cfDNA screening increases the false positive rate. This means that more people would receive a positive (high risk) screen result even though the baby does not actually have the condition. This would result in more people having diagnostic tests, with associated risk of miscarriage. Current recommendations do not support the routine inclusion of screening for microdeletion and microduplication syndromes in NIPT/cfDNA screening.
Remember…
Non-Invasive Prenatal Testing (NIPT), also known as cfDNA screening, is a test to estimate the chance that the baby a person is carrying has Down syndrome and other specific genetic conditions.
NIPT/cfDNA screening is available to all pregnant people. Some provincial prenatal screening programs will pay for NIPT/cfDNA screening when certain increased risk criteria are met. Where provincial funding is not available, people can self-pay for NIPT/cfDNA screening. Prices vary by company, the average cost being around $500.
Benefits: NIPT/cfDNA screening is much better at detecting Down syndrome and other specific genetic conditions than conventional prenatal screening (e.g. Enhanced First Trimester Screening). NIPT/cfDNA screening has a lower false positive rate than conventional prenatal screening. Higher detection and lower false positive rates mean that fewer people will need to have follow-up invasive testing which is associated with a small risk of pregnancy loss.
Limitations: NIPT/cfDNA screening is not diagnostic, meaning that it cannot tell with certainty whether or not the baby a person is carrying has Down syndrome or another genetic condition. A person who receives a high risk or positive NIPT/cfDNA screening result will be offered diagnostic testing by amniocentesis or chorionic villus sampling to confirm or rule out the diagnosis. NIPT/cfDNA screening cannot detect all possible genetic conditions. There is no screening or diagnostic test which can guarantee a baby that does not any birth difference or any genetic condition. A person who receives a low risk NIPT/cfDNA screening resultmay still be offered additional counselling or testing depending on why they were originally offered NIPT/cfDNA screening.
What do my screening results mean?
A: Screening results using Enhanced First Trimester Screening as an example:
Enhanced First Trimester Screening (eFTS) calculates the chance that the baby has Down syndrome or trisomy 18. It does not screen for open neural tube defects or any other condition. eFTS uses the age of the pregnant person/egg donor at the time of delivery, the size of the nuchal translucency (NT) on a first trimester ultrasound, and the levels of certain hormones in the pregnant person’s blood that are being produced by the current pregnancy. A risk is then calculated estimating the chance that the baby has either condition. Generally, for eFTS, a risk greater than 1/350 (~0.3%) is considered screen positive and any risk lower than this is a screen negative. For more on eFTS see Section I have decided. I do want to have prenatal screening, now what?.
What if my eFTS result is a screen NEGATIVE?
This is reassuring. This means that the chance that your baby has Down syndrome or trisomy 18 is LOWER than the screening cut-off (for example less than 0.3% or 1/350). Note that the screening cut-off may vary by laboratory and condition.
What do I do next?
Remember eFTS is only intended to screen for Down syndrome and trisomy 18. eFTS is not intended to screen for any other conditions. An ultrasound is recommended for all individuals expecting a baby at about 18 20 weeks of pregnancy to look at the baby’s growth and development, regardless of prenatal screening results. While most babies are born without a birth difference, 1 in 25 babies in Canada will be born with a difference that may require medical or surgical intervention. It is important to remember that no test can detect every type of congenital anomaly (birth difference).
What if my eFTS result is a screen POSITIVE?
This means that the chance of your baby having Down syndrome or trisomy 18 is HIGHER than the screening cut- off (for example greater than 0.3% or 1/350). This result does not necessarily mean that your baby has one of these genetic conditions. Remember that most babies are born without anomalies.
A nuchal translucency (NT)measurement greater than 3.5mm is an automatic screen positive for Down syndrome and certain other conditions and should prompt a referral for genetic counselling.
Is an eFTS screen POSITIVE result accurate?
eFTS will identify most (about 85- 90%) pregnancies where the baby has Down syndrome.
eFTS does not perform as well when detecting trisomy 18, however it will identify most pregnancies with trisomy 18.
While eFTS is excellent at identifying most pregnancies where the baby has Down syndrome or trisomy 18, most screen positive results turn out to be false. This is called a FALSE POSITIVE and is identified either by diagnostic testing or by the birth of a baby who does not have the condition.
eFTS does not screen for open neural tube defects.
eFTS is not meant to screen for any other disorders.
B: Screening results using non-invasive prenatal testing (NIPT) as an example:
NIPT/cfDNA screening is a newer and more accurate way to screen for Down syndrome, trisomy 18, trisomy 13 and sex chromosome differences in a pregnancy. NIPT examines DNA in the pregnant person’s blood that comes from the pregnancy.
What if my NIPT/cfDNA screening result is NEGATIVE?
This is very reassuring. Generally, an NIPT/cfDNA screen NEGATIVE result is reported as LOW RISK (less than 1 in 10,000 chance). The chance that your baby has Down syndrome, trisomy 18, trisomy 13 or a sex chromosome difference is LOWER than that. NOTE: In twin pregnancies, it is not possible to screen for sex chromosome differences.
What do I do next?
Remember NIPT/cfDNA screening is only intended to screen for Down syndrome, trisomy 18, trisomy 13 and sex chromosome differences. You may be offered a late first trimester ultrasound (11-14weeks). Additionally, an ultrasound is recommended for all individuals expecting a baby at about 18 20 weeks of pregnancy to look at the baby’s growth and anatomy, regardless of prenatal screening results. While most babies are born without a birth difference, 1 in 25 babies in Canada will be born with a difference that may require medical or surgical intervention. It is important to remember that no test can detect every type of anomaly.
If you had NIPT/cfDNA screening because a first trimester ultrasound found the nuchal translucency measurement was 3.5mm or greater, a referral for genetic and/or maternal fetal medicine consultation is still recommended. Additional testing and/or follow-up may still be offered for example a special ultrasound of the baby’s heart, or other types of genetic testing.
What if the risk number reported is not less than 1 in 10,000?
If you received a risk result other than less than 1 in 10,000 (e.g. another low risk value or a borderline risk) you should discuss this result with your health care practitioner or genetic counsellor. This test is still relatively new and additional follow up testing and/or counselling may be needed.
What if my NIPT/cfDNA screening test fails?
Occasionally NIPT/cfDNA screening may fail and no result is reported. There are various reasons why a test may fail, What are the limitations of NIPT/cfDNA screening? for more. In this event, you may be asked for a new blood sample. Most of the time a result will be available after this second try. This can delay results and so it would be important to consider if the result would be received in a timely manner for decision-making. If the second try is also unsuccessful you may be offered genetic counselling to discuss this and additional testing options.
What if my NIPT/cfDNA screening result is POSITIVE?
An NIPT/cfDNA screen POSITIVE result is generally reported as HIGH RISK (greater than 99% chance). NIPT/cfDNA screening has a very low false positive rate meaning that further testing is expected to confirm the diagnosis and most screen positives will be true positives.
However, NIPT/cfDNA screening is not a diagnostic test and there is still a small chance that a high-risk result is false. In the event of a screen positive NIPT/cfDNA result, diagnostic testing is recommended prior to any permanent action (e.g. choosing to end the pregnancy). Information gained from diagnostic testing is also helpful for future counselling about recurrence risks in future pregnancies. If people expecting a baby would continue the pregnancy regardless of diagnostic results, chromosomal testing can be arranged after the baby is born.
Is an NIPT/cfDNA screen POSITIVE result accurate?
NIPT/cfDNA screening will identify about 99% of pregnancies (99 out of 100) where the baby has Down syndrome. N I PT/cfDNA screening does not perform as well when detecting trisomy 18 and even less so when detecting trisomy 13 and sex chromosome differences, however it is still considered a superior screen to traditional prenatal screening (Table 1) for these conditions.
What are the next steps if my prenatal screening test is POSITIVE?
If your prenatal screening result is reported as positive or high risk for a chromosome condition (i.e. Down syndrome, trisomy 18), you are likely to be offered an appointment with a genetic counsellor. There you will discuss what this result means and your options, including no further testing, or a diagnostic test such as amniocentesis or chorionic villus sampling (CVS). Genetic counsellors can help you understand your options and make the decision that is right for you. They will support your decision no matter what you decide.
If your result is screen positive for a neural tube defect, you may have the option of a detailed ultrasound at 18 to 20 weeks instead of amniocentesis. This will vary depending on where you live.
There are many factors that influence peoples’ decisions to choose one option over another following a positive prenatal screening result. Some important considerations are:
time is an important consideration in pregnancy decisions
in Canada, while there are no legal restrictions on ending a pregnancy by medical termination, the availability is different in each city. Typically, before 22 weeks of pregnancy, medical termination can be accessed. After this, special arrangements may need to be made. Your health care practitioners and/or genetic counsellor will be able to help you learn what is available to you.
The risk reported by the screening test
a screen positive risk score of 1/200 (0.5%) versus a screen positive risk score of 1/2 (50%) may weigh differently on peoples’ decisions
When deciding about whether or not you wish to proceed with diagnostic testing you should consider what you might do in the event that the results say your baby does have the condition. You do not have to decide before testing what you would do in the event a diagnosis is confirmed; however preparing yourself to make such a decision can be important. Your health care practitioner will also discuss your choices with you. You may want to discuss this with your partner, friends, family, spiritual leader or other supports.
Consider…
Based on the risk number you have been given, whether it is a 1 in 10 (10%) or a 1 in 100 (1%), can you continue your pregnancy with that level of uncertainty or do you need to know for sure?
What if diagnostic testing has been offered to me?
Diagnostic procedures
Where screening tests calculate a risk (what is the chance), a diagnostic test/procedure will rule in or rule out for sure whether or not a baby has one of the conditions. There are two common diagnostic tests that are offered: chorionic villus sampling (CVS) and amniocentesis. Whereas prenatal screening tests are considered non-invasive as they pose no risk to a pregnancy, diagnostic tests are considered invasive because they are associated with a small procedural risk – an increased chance to lose the pregnancy (miscarriage).
Chorionic villus sampling (CVS)
What is chorionic villus sampling?
Chorionic villus sampling (CVS) is a procedure where a small piece of the placenta is taken and tested. Chorionic villi (see image on the right) attach the placenta to the uterus wall. The placenta is made from the fertilized egg and is expected to have the same genetic information as the baby. CVS is not available in all regions. Talk to your health care practitioner to see if this is an option for you. CVS cannot detect open neural tube defects.
When is a CVS carried out?
CVS is usually performed between 11 and 13 weeks of pregnancy.
What is the risk associated with CVS?
Both CVS and amniocentesis have been associated with a slightly increased chance of losing the baby following the procedure (miscarriage). The chance of miscarriage after a CVS or an amniocentesis is 0.5 to 1% (about 1 in 100 or less).
Both CVS and amniocentesis have been associated with a slightly increased chance of losing the baby following the procedure (miscarriage). The chance of miscarriage after a CVS or an amniocentesis is 0.5 to 1% (about 1 in 100 or less).
What should I expect at my CVS appointment?
CVS is an outpatient procedure, meaning that you will not need to stay overnight in the hospital. You will be told to have a full bladder. There are two methods to collect a sample from the placenta; either through the vagina or the abdomen. Both methods use ultrasound as a guide the entire time.
Through the vagina, using ultrasound, a speculum is inserted (just like a Pap test). Then a very thin, plastic tube is inserted up the vagina and into the cervix. The tube is guided up to the placenta and a small sample is removed.
To collect a sample through the abdomen, a thin needle is inserted through the abdominal wall, using ultrasound to guide the needle tip to the placenta.
Will it be painful?
Most people describe the procedure as uncomfortable rather than painful. In general, no medication or anesthetic is given. Through the vagina, the discomfort is similar to that with a Pap test. Through the abdomen, the pain from the needle is similar to having a blood sample drawn. The needle is a bit thicker and a numbing cream may be applied to the skin prior to the procedure. You can expect to experience some uterine cramping during the procedure.
Amniocentesis
What is amniocentesis?
Amniocentesis is a procedure where a small sample of amniotic fluid (the fluid that surrounds the baby) is removed and tested. Usually only about 1-2 tablespoons are taken. Amniotic fluid contains fetal cells: skin cells and others cells that are naturally shed by the baby.
When is an amniocentesis carried out?
The ideal timing is between 15 and 18 weeks to allow opportunity for the procedure, results and decision making. An amniocentesis can, however, be performed any time after 15 weeks.
What is the risk associated with amniocentesis?
Both CVS and amniocentesis have been associated with a slightly increased chance of losing the baby following the procedure (miscarriage). The chance of miscarriage after a CVS or an amniocentesis is 0.5 to 1% (about 1 in 100 or less).
What should I expect at my amniocentesis appointment?
Amniocentesis is an outpatient procedure, meaning that you will not need to stay overnight in the hospital. You may be told to have a full bladder, but this will likely depend on how far along in pregnancy you are.
To collect a sample of amniotic fluid, using ultrasound guidance the entire time, a thin needle is inserted through the abdominal wall into a pocket of fluid (not near the baby) and fluid is extracted.
Will it be painful?
Most people describe the procedure as uncomfortable rather than painful. In general, no medication or anesthetic is given. The pain from the needle is similar to that when having a blood sample drawn. You can expect to experience some uterine cramping during the procedure.
Remember…
Amniocentesis and chorionic villus sampling (CVS) are procedures where a sample from the pregnancy is obtained for prenatal diagnostic genetic testing.
Through a diagnostic test, you can learn for sure whether or not your baby has the condition tested positive for by prenatal screening (Down syndrome, trisomy 18, trisomy 13, sex chromosome difference, open neural tube defect).
*CVS cannot detect neural tube defects. Closed neural tube defects may not be detected by amniocentesis.*
These tests are associated with a small chance to lose the pregnancy (miscarriage).
Other genetic conditions can also be detected by these tests.
Your genetic counsellor or prenatal care provider will discuss these testing options with you in more detail and help you to understand the right test for you.
A word about unexpected news
If you have diagnostic testing and the results confirm that your baby has Down syndrome, trisomy 18 or open neural tube defect, genetic counsellors are available to help you discuss your options: continuing the pregnancy, adoption or choosing to end the pregnancy.
Making a decision is not easy. Genetic professionals can help you find resources, such as support groups, that may be helpful to you during and after your decision-making. There are health care practitioners available to help you and offer support no matter what decision you make.
The choice is yours.
A prenatal screening process map
Online resources
To find your local provincial prenatal screening program go to GECKO > Resources for the Public > Links to provincial programs
For more resources on an Introduction to Genetics, try:
This guide was written by a multidisciplinary team and with input from new parents. We are always updating and revising our resources. If you have feedback for us, please do reach out to GECKO@cheo.on.ca
All images are open-source. Links to their original site are attached to each photo
Additional resources
Introduction to genetics and prenatal testing after a diagnostic test (chorionic villus sampling (CVS) or amniocentesis).
Introduction to genetics
Each cell of the body, be it a hair, liver, or heart cell, contains an individual’s genetic information. Genetic information is like a blueprint, containing all the necessary instructions to build a person and for the lifelong growth and development of that individual.
Genetic information is packaged into structures called chromosomes. Typically, inside each cell there are 23 pairs of chromosomes (e.g. two copies of chromosome 1, two chromosome 2, etc.), for a total of 46 chromosomes in each cell (Figure 1). One chromosome from each pair is inherited from each genetic parent.
Mature egg and sperm cells typically have only 23 chromosomes. When an egg cell and a sperm cell mature, they undergo a division process into two identical daughter cells, and each chromosome pair separates. One copy from each chromosome pair goes into each new daughter cell (Figure 2a).
The testes will constantly produce new sperm cells over one’s life. On the other hand, all the eggs the ovaries will ever produce are present at the birth of that individual. These eggs are ‘frozen’ mid-division and, at ovulation, typically one egg will fully divide. These eggs age as the individual ages. Over time, there is an increased chance for there to be an error in the division process, where a chromosome pair does not separate correctly (Figure 2b). In this case the egg contains an extra or missing chromosome. There is nothing that an individual can do to cause or to prevent this. While there is a chance to have a baby born with a chromosome difference at any age; this chance increases as the eggs age (Table 3). An example of a chromosome condition is Down syndrome. An individual with Down syndrome has an extra copy of chromosome 21 (trisomy 21, three copies of chromosome 21) and has 47 chromosomes in total.
A chromosome may contain hundreds to thousands of genes. Genes are the individual instructions to make important proteins for a healthy individual. For example, insulin is an important protein the body makes to control sugar levels. The gene, or instruction, for insulin is located on chromosome 11. There are about 20,000 genes in total and it is important to have the right number of genes and the right set of instructions for healthy growth and development.
Table 3. Pregnant person/egg donor’s (in the case of donated egg) age at delivery and the chance to have a baby with Down syndrome and other chromosome conditions.
Pregnant person/egg donor’s age (Years)Chance to have a baby with Down SyndromeChance of any chromosome condition including trisomy 18 and Down Syndrome
20
1 in 1,484 (~0.1%)
1 in 530 (~0.2%)
25
1 in 1,362 (~0.1%)
1 in 480 (~0.2%)
30
1 in 994 (~0.1%)
1 in 390 (~0.3%)
35
1 in 403 (~0.3%)
1 in 180 (~0.6%)
40
1 in 98 (~1%)
1 in 65 (~0.2%)
45
1 in 38 (~3%)
1 in 19 (~5%)
Diagnostic tests
You can read about the procedures to obtain a prenatal sample in the previous section Diagnostic procedures but what about the testing that is performed on that sample?
Quantitative fluorescence PCR (QF-PCR)
QFPCR is a laboratory test used to precisely measure the amount of DNA present. This test may also be called Rapid Aneuploidy Detection (aneuploidy, refers to genetic conditions< where there are extra or missing whole chromosomes) or RAD. Generally, this is the first test performed on a prenatal sample (amniotic fluid or chorionic villus sample). This test can tell accurately whether the baby has or does not have Down syndrome, trisomy 18, trisomy 13 or a sex chromosome difference. This is the recommended diagnostic test for pregnancies where there is an increased risk for one of the above-mentioned chromosome conditions. Results from this test are usually available within one week.
Fluorescent in situ Hybridization (FISH)
FISH is a laboratory technique used to visualize pieces of DNA. FISH uses small pieces of DNA that are labelled with glowing (fluorescent) tags. These tagged pieces of DNA (probes) will attach to specific parts of specific chromosomes. Like QFPCR, FISH is a technique used to measure DNA. For example, a probe is designed to attach to chromosome 21, if the sample is from someone who has Down syndrome then three probes will attach to the three copies of chromosome 21. If the sample is from someone who does not have Down syndrome then only two probes will attach. This test will tell for certain whether the baby has or doesn’t have Down syndrome, trisomy 18, trisomy 13 or a sex chromosome difference. Results from this test are usually available within one week.
Karyotype
Karyotyping is a laboratory technique used to examine all the chromosomes, evaluating whether there are any major chromosomal differences, including whole extra or missing chromosomes, large extra or missing pieces of a chromosome and structural changes in the chromosomes (e.g. chromosomes that are stuck together or that have exchanged large pieces). Karyotype testing will follow an abnormal result reported by QFPCR or FISH. Results from this test usually take about 2-3 weeks.
Chromosomal Microarray
Chromosomal microarray (CMA) is a newer technology that has recently been added to the prenatal testing menu. In addition to looking at extra or missing whole chromosomes, CMA will also detect very tiny extra or missing pieces of genetic information (microduplications/microdeletions). The potential for complex results and the detection of both unexpected and uncertain findings warrants the need for comprehensive genetic counselling before and after undergoing this test.
Multigene panel
This is a genetic test that reads through multiple genes, letter by letter, at the same time. Gene panels contain carefully selected genes that are known to be associated with specific health, physical or developmental issues, such as a gene panel for epilepsy, for heart conditions or for dwarfism (skeletal dysplasia). A multigene panel may be considered when your genetic health professional suspects a genetic condition.
Whole exome sequencing and whole genome sequencing
This is the latest genetic test that involves reading through all the genes at the same time, all 20,000. The exome refers to the part of the genes that are actually read to make the protein, coding region. The exome makes up only about 1% of all the genetic information. The other part of the genes are not read to make the protein, non coding regions. These parts are called introns. Whole exome sequencing is testing that reads through all the coding regions of the genes. Whole genome sequencing is testing that reads through all the coding and non-coding regions of the genes.
Have some questions about how Canada’s genetic non-discrimination act works and what it means for your practice? Check out Canadian Family Physician for a free access article:
Cowan JS, Kagedan BL, Graham GE, Heim-Myers B, Bombard Y. Health care implications of the Genetic Non-Discrimination Act: Protection for Canadians' genetic information. Can Fam Physician. 2022 Sep;68(9):643-646. PMID: 36100377
GECKO on the run: A 4-page, evidence-based summary for healthcare providers. Features a bottom line, genomic test results and next steps, brief description of genomic test types, considerations when ordering genomic testing. [Feb 2023]
Point of care tool: Contains definitions of common genomic test results and next steps, as well as additional considerations. [Feb 2023]
A resource developed for pregnant persons and their providers. Everything you wanted to know about screening from deciding whether or not have it, to results…
