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Below are point of care tools to facilitate ordering first-tier genetic testing for neurodevelopmental disorders (NDDs) in each province. (updated June 2024)
Download the PDF here. For point of care tools to facilitate ordering of first-tier genetic testing in your province, see here. For a comprehensive overview of neurodevelopmental disorders and genetics, see the GECKO deep dive here. [May 2024]
Bottom line: Neurodevelopmental disorders (NDDs) are a group of conditions which include autism, global developmental delay (GDD) and intellectual disability (ID), as well as attention deficit hyperactivity disorder (ADHD), specific learning disorders (LD), and others.
An NDD may have a genetic cause, such as a genetic syndrome, or complex inheritance with genetic susceptibility factors. An identifiable genetic etiology is more likely in those with co-occurring health conditions or those who have a family history of NDDs.
Genetic testing is indicated for all:
autistic individuals.
individuals with unexplained GDD and/or ID.
individuals with an NDD and co-occurring features suggestive of a possible genetic condition.
Genetic testing is not indicated for those with isolated ADHD, LD, speech delay or other isolated NDD.
The Canadian College of Medical Geneticists 2023 Position Statement recommends first-tier genetic testing be organized by non-genetics clinicians before or concurrent with a referral to genetics. This includes chromosomal microarray and, in some cases, Fragile X syndrome testing.
Identifying the genetic etiology of an NDD may provide answers for families, inform recurrence risk and medical management. Individuals with a positive result on first-tier testing benefit from referral to a genetics specialist. Negative first-tier genetic testing does not rule out the possibility of a genetic contribution and referral to a genetics specialist for consideration of second-tier testing is recommended, unless the indication for testing was isolated autism. Genetic testing may yield uncertain or unexpected results, in which case a referral to a genetics specialist would be recommended.
Periodic reassessment and possible re-referral to Genetics is suggested when no genetic etiology is identified using current testing approaches.
What are neurodevelopmental disorders (NDDs)?
NDDs are conditions that impact the development and function of the brain leading to general or specific impairments of intellectual, motor, language, and/or social skills or abilities. Onset is early in childhood development and impairments can continue throughout life. NDDs include autism, intellectual disability (ID) and global developmental delay (GDD), attention deficit hyperactivity disorder (ADHD), communication disorders, specific learning disorders, and motor and tic disorders.
What causes NDDs?
Once an NDD diagnosis has been established, an etiological diagnosis can be explored.
Autism: The etiology of autism is typically thought to be multifactorial. Genetic and non-genetic (i.e. environmental) susceptibility factors and their interactions contribute in an additive way to the likelihood of an individual being autistic. Some genetic susceptibility factors confer a high chance of autism, while others confer a lower or moderate chance. A genetic susceptibility factor may not be specific to autism and may also predispose to other NDDs. Environmental factors can contribute varying levels of susceptibility, but overall contribute less to autism than genetic factors.
Less commonly, autism can be a feature of a genetic syndrome. This is when autism is accompanied by a distinctive pattern of co-occurring health, behavioural, learning, and/or physical features. Examples include Fragile X syndrome, Rett syndrome, and Cowden syndrome.
Genetic variants associated with autism susceptibility can be inherited from a parent or can be de novo (a genetic variant occurring for the first time in an individual that has not been present in previous generations).
Global developmental delay and intellectual disability (GDD/ID): There are many possible causes of GDD/ID, including: genetic conditions, central nervous system malformations, illness/infection, prenatal exposure to teratogens, complications at birth, etc. There are numerous genetic etiologies, some associated with additional features (syndromic) and some not. Genetic variants associated with GDD/ID could be inherited from a parent or could be de novo. Some genetic variants may be sufficient in isolation to cause GDD/ID whereas others may act as susceptibility factors in a multifactorial inheritance model.
Other Neurodevelopmental Disorders: Many NDDs likely have genomic contributions. However, there is limited evidence regarding the likelihood of a genetic diagnosis for isolated NDDs other than autism, GDD and/or ID.
Who may benefit from a genetic assessment?
If an individual has clinical features suggestive of a specific genetic condition such as Rett syndrome, referral to a genetics specialist is suggested for evaluation and consideration of targeted genetic testing.
As the demand for genetic consultation is high and the wait time can be long, the Canadian College of Medical Geneticists (CCMG) recommends that, prior to a request for a genetic assessment for an individual with an NDD, the primary care practitioner or the most responsible healthcare practitioner offers and orders first-tier genetic testing.
Referral for a genetic assessment with first-tier genetic test results (positive, negative, uncertain or unexpected) is recommended unless the only indication for testing was isolated autism and the results were negative. Consider periodic reassessment when no genetic etiology is identified as genetic technology and genomic knowledge evolve.
In Manitoba, Newfoundland and Labrador, and Saskatchewan, first-tier genetic testing cannot currently be ordered by primary care clinicians. Referral to Genetics or Developmental Pediatrician for assessment is required.
Who to consider for first-tier genetic testing?
The goals of genetic testing are to investigate the underlying etiology of an existing diagnosis, inform medical care and prognosis, provide recurrence risk and inheritance information, and identify support resources. Genetic testing will not confirm or refute an established NDD diagnosis.
The Canadian College of Medical Geneticists (CCMG) 2023 Position Statement recommends that genetic testing be offered to all:
autistic individuals.
individuals with unexplained GDD and/or ID (regardless of severity).
individuals with other NDDs plus syndromic features.
Syndromic features may include dysmorphic features, congenital malformations, unexplained growth abnormalities, medical co-morbidities, or features of a metabolic condition. More details can be found in the GECKO deep dive. Resources for clinicians> Neurogenomics> Neurodevelopmental conditions
Genetic testing is not recommended for those with isolated NDDs other than autism, GDD, or ID.
What are first-tier genetic tests for NDD?
First-tier genetic tests for the indications above are chromosomal microarray and, in some cases, Fragile X syndrome.
Chromosomal microarray (CMA): CMA detects tiny gains and losses in the amount of chromosomal material. The types of variations detected by CMA include copy number variants (CNVs, variation in the number of copies of a specific segment of DNA, a micro-deletion or micro-duplication) and most aneuploidies (extra or missing whole chromosomes). CMA has a higher diagnostic yield than a karyotype for individuals with GDD/ID and autism and is thus the preferred genetic test.
Fragile X syndrome (FXS) testing: FXS is an X-linked condition caused by expansion of a repetitive nucleotide sequence in the FMR1 gene resulting in silencing of the gene. FXS can affect individuals regardless of sex assigned at birth, although the clinical presentation in those assigned female at birth is highly variable. As per CCMG statement, consider offering FXS testing to individuals with a diagnosis of autism, GDD and/or ID AND one or more of the following features:
Macro-orchidism
Relative or mild macrocephaly
Large or prominent ears, long or narrow face, tall forehead, high arched palate, prominent jaw
Soft velvety hands, redundant skin on dorsum of hands, hyperextensible joints, pes planus, mitral valve prolapse
Maternal relatives with a diagnosis of autism, GDD and/or ID
Maternal relatives assigned female at birth with premature menopause or ovarian insufficiency
Maternal relatives with adult-onset tremor, ataxia, or parkinsonism
Maternal relatives with a known diagnosis of FXS or FXS related condition
Metabolic/biochemical testing: Inherited metabolic conditions associated with NDDs are individually rare. Most individuals will have additional suggestive features. Biochemical screening is only suggested for those with ‘red flags’ for these conditions such as developmental regression/plateau, abnormal neurological exam, intractable seizures, organomegaly, and/or movement disorders. Consider urgent referral to a metabolic/genetic specialist if a metabolic condition is suspected.
Second-tier genetic tests: In the absence of a positive result on first-tier testing, a geneticist may offer additional testing such as a multigene panel or exome sequencing (ES) following a thorough assessment.
How is genetic testing for NDD arranged?
GECKO point of care tools are available to facilitate discussion of genetic testing and explain how to order genetic testing, including links to laboratories and requisitions across Canada.
Patient meets eligibility criteria.
Patient accepts testing after value-based discussion weighing benefits and considerations.
Download and complete the Requisition of the regional/provincial laboratory to order CMA.
Complete with as much information as possible, checking all applicable boxes, and include available family history (even if non-contributory). The laboratory scientists will use all available clinical information to interpret results.
Consider making a plan with your patient about how results will be disclosed e.g. by phone, an in-person appointment.
Genetic test results can take 4-8 weeks, depending on the laboratory. If results could affect an ongoing pregnancy, you can request that they are expedited.
Determine if FXS testing should also be offered and coordinate the blood draws with the appropriate requisition.
*Referral to Genetics or Developmental Pediatrician for assessment is required for clinicians in Manitoba, Newfoundland and Labrador, and Saskatchewan.
The first-tier tests are typically performed by hospital-based genetics laboratories. CMA is a cytogenetic test and FXS is a molecular genetic test. One requisition is usually required for each test as testing will be performed in separate laboratories.
If a blood draw is anticipated to be challenging, many online resources are published to assist parents and practitioners in preparing, such as:
What are the benefits and considerations of genetic testing for NDDs?
The likelihood of identifying a genetic cause depends on the indication for testing, whether an individual has any co-occurring health conditions, and/or any family history of NDDs.
Benefits
A positive test result (pathogenic or likely pathogenic variant) leading to a genetic diagnosis may:
provide a causal explanation for the NDD diagnosis. For some, this may relieve parental guilt and/or promote acceptance of an NDD diagnosis.
aid in preparing for an individual’s future care and needs.
inform medical care in a small subset of individuals. For example, by facilitating targeted surveillance for other medical conditions (e.g. cancer) known to be associated with the genetic diagnosis.
provide information about inheritance and recurrence risk.
allow identification of condition-specific support resources for individuals and families.
Considerations
Learning about genetic testing results can be emotionally challenging.
An uninformative result may be disappointing or frustrating.
Unclear or unexpected results are possible and may be distressing.
An identified inherited cause may produce feelings of parental guilt.
Some individuals worry about stigma associated with a genetic diagnosis.
Due to limitations in current genomic knowledge and technology, a negative result does not rule out a genetic contribution, or the possibility of having another child with an NDD.
Result may not inform prognosis/medical management even if a genetic explanation is found.
Information discovered may have implications for the health of relatives.
In the past, genetic results could have impacted one’s ability to obtain life, long-term care, or disability insurance. Today, in Canada, a Genetic Non-Discrimination law protects Canadians and their genomic information from discrimination.
Authors: C Aldridge, MS CGC, S Morrison MS CGC, JE Allanson MD FRCPC FCCMG, S Walji MD CCFP MPH and JC Carroll MD CCFP
(these resources replace previous content on autism spectrum disorder)
GECKO on the run:A 4-page, evidence-based summary for clinicians. Features a bottom line, causes of NDDs including autism spectrum disorder and fragile X syndrome, benefits and considerations of genetic assessment and testing, when and how to offer first-tier genetic testing. (May 2024)
GECKO deep dive: A 21-page, comprehensive evidence-based resource for clinicians. Features a bottom line, causes of NDDs including autism spectrum disorder and fragile X syndrome, benefits and considerations of genetic assessment and testing, types of genetic investigations and results, when and how to offer first-tier genetic testing. (May 2024)
Point of care tool: To facilitate ordering first-tier genetic testing in your province. (June 2024)
Resource for patients and families – coming soon
GECKO aims to aid the practicing non-genetics clinician by providing informed opinions regarding genomic conditions, services and technologies that have been developed in a rigorous and evidence-based manner with periodic updating. The content on the GECKO site is for educational purposes only. No resource should be used as a substitute for clinical judgement. GECKO assumes no responsibility or liability resulting from the use of information contained herein.
For a comprehensive guide on prenatal screening including enhanced first trimester screening, next steps following results, more questions to consider, please see this Guide.
What is prenatal screening?
Prenatal screening is about checking the health and development of your baby before it is born. It means getting information to better understand the chances of certain health conditions for your baby. Prenatal screening cannot tell you for certain if you baby does or does not have a condition.
Prenatal screening can involve blood work and/or an ultrasound.
This resource is about Non-Invasive Prenatal Testing, also called NIPT.
Can NIPT hurt me or my baby?
No.
NIPT is a blood test. There is no harm to you or the baby.
Do I have to have NIPT or any prenatal screening?
No.
Prenatal screening is your choice. While every pregnant person should be offered the choice to have prenatal screening, it is everyone’s personal choice to accept or not.
Can NIPT tell me if my baby will be healthy?
No.
There is no test to guarantee a healthy baby. NIPT will only look for the chance the baby has one of the specific genetic conditions mentioned below (Down syndrome, trisomy 18, trisomy 13 or a sex chromosome difference).
When can I have NIPT?
The blood can be drawn anytime after 10 weeks’. Results come back in 7-10 business days. If the blood is drawn too early, the test may not work.
What does NIPT look for?
NIPT looks at DNA in your blood. While most (90%) of the DNA in your blood is yours, some (~10%) comes from the pregnancy (specifically, the placenta).
NIPT will report on how likely your baby has a specific genetic condition: Down syndrome, trisomy 18, trisomy 13. Every pregnant person has a chance to have a baby with one of these conditions, and that chance increases with the age of the person (or egg in the case of a donor) when the baby is born. Nobody can cause or prevent these conditions; they occur by chance.
NIPT can also report on the sex chromosomes (male or female). Sometimes NIPT will report that there might be an extra or missing sex chromosome.
A Genetics Minute:
Inside every cell of your body- blood cells, brain cells, heart cells – there is your DNA. This is a library of recipes needed to make important proteins that have jobs for development, maintenance, and health. These ‘recipes’ are called genes. There are about 21,000 genes in your DNA library. The genes are arranged like beads on a string into structures called chromosomes. Typically, a human cell will have 23 pairs of chromosomes numbered 1 to 22, and the 23rd pair are called the sex chromosomes.
Most (99.9%) of the DNA library is the same between person to person, but still this small bit of difference makes each of us unique. Sometimes a difference in our DNA does not have any effect on our health/development, but sometimes a difference as big as a whole extra or missing chromosome containing thousands of genes can have significant effect on health/development.
How good is NIPT?
NIPT will identify almost all pregnancies where the baby has Down syndrome, trisomy 18, or trisomy 13. It is the best screening test to identify Down syndrome.
What will the results say?
The results will most often say that there is a very low chance for the baby to have one of these conditions (less than 0.01% or 1 in 10,000). Sometimes the results will say there is a very high chance the baby has one of the conditions above (higher than 99%). Sometimes the report will say no result which means that the laboratory was not able to get a clear result.
What do I do if the results are low risk?
If your NIPT result is low risk, you can feel reassured that your baby does not have any of the conditions screened for. You will still be offered an ultrasound in the second trimester (18-22 weeks’) to look at your baby’s growth and development.
If there is another reason to suspect a genetic difference in your baby (e.g. something seen on ultrasound or something in your family history), you may still be offered an appointment with a genetics specialist and/or high-risk obstetrician to talk about other testing options.
What do I do if the results are high risk?
If the results are high risk, this does not mean your baby has the condition, but it does means there is a high chance. You will be offered an appointment with a genetics specialist, usually via telephone. Here you will talk about the result, the condition, and next steps such as a diagnostic test to know for sure if your baby does or does not have the condition. Your health care practitioners will support any choice that is right for you.
What do I do if there is no result?
If there is no result, the laboratory might ask that a new blood sample is sent to try again. When this happens, most of the time a result will then be available. Sometimes, it is not possible to get any result from NIPT. In this case, you could be offered an appointment with a genetics specialist to talk about why NIPT can fail and what are possible next steps.
Can NIPT tell me any other information?
Rarely, however because NIPT testing is looking at DNA from both the pregnancy and from you, a result could reveal information about your DNA or health. In these cases, an appointment with a genetics specialist would be offered.
Is there anything else to think about?
Your family history.
Everyone has a chance to have a baby born with a difference or to develop a medical condition, but that chance can be higher if you have a family history of such a difference or medical condition.
If there is something in your family (or pesonal) history - for example a known genetic condition, a close relative* (or personal history) with:
intellectual disability
born with one or more differences at birth that needed surgery (like a hole in the heart) or other medical intervention
young children or babies that passed away unexpectedly or where the cause is not known
who had more than 3 pregnancy losses
discuss with your healthcare practitioner and a referral for a genetic consultation for you or a relative could be considered.
*A close relative would be a parent, sibling, grandparent, aunt/uncle
Is prenatal screening right for me?
Some questions to consider before NIPT:
Do I want to know if my baby has one of these conditions before birth?
What would the results mean for me in this pregnancy?
Would I consider ending a pregnancy that had one of these conditions?
Would it be important for me to plan, identify support, and get prepared for a baby that has one of these conditions, before the baby is born?
Would have a diagnostic test? Would I fly/travel to another city if needed?
A diagnostic test the only way to know for sure if the baby has the condition before birth (i.e. amniocentesis or chorionic villus sampling). These tests have a small risk to lose the pregnancy (miscarriage).
Down syndrome (also called trisomy 21) is a genetic condition where there is an extra copy of all or a portion of the 21st chromosome. People with Down syndrome are individuals who are as unique and highly variable as anyone else. This extra chromosome 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 about 60 years. About 1 in 781 babies born has Down syndrome. The chance of having a child with Down syndrome increases with the pregnant person’s age. For more information on Down syndrome, visit the Canadian Down Syndrome Society website.
Trisomy 18 is a genetic condition where there is an extra copy of all or a portion of the 18th chromosome. 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). About 1 in 6,000 babies born has trisomy 18. The chance of having a child with trisomy 18 increases with the pregnant person’s age. For more on trisomy 18, visit The Trisomy 18 Foundation website.
Trisomy 13 is a rare genetic condition where there is an extra copy of all or a portion of the 13th chromosome. Trisomy 13 occurs in approximately 1 in 10,000-25,000 live-born infants. Everyone with trisomy 13 is unique however there is a recognizable pattern of physical differences such as small head, cleft lip and/or palate, small eyes or absent eye as well as serious intellectual disabilities and birth differences that can affect many organ systems (e.g. brain, heart, kidneys). Most pregnancies with trisomy 13 will miscarry. About 5-8% of infants will survive past 1 year. With significant medical intervention longer survival has been reported. For more on trisomy 13, visit The Support Organization for Trisomy 18, 13 and Related Disorders (SOFT) website.
There are several conditions with sex chromosome differences. These types of genetic differences are common and happen in about 1 in 500 individuals. There is a lot of variation between the different conditions depending on which chromosome is extra or missing (X and/or Y). Some features maybe as mild as tall or small height. There may be differences in development such as delayed speech or learning differences. There may be health issues involving puberty or the heart. If your NIPT result reports a high risk for a sex chromosome difference, you will be offered an appointment with a genetics specialist to talk more about the condition and next steps. For more on sex chromosome differences, visit The Association for X and Y Chromosome Variations (AXYS) or the Turner Syndrome Society of Canada for more.
Where screening tests calculate a risk (what is the chance), a diagnostic test 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). Because of the nature of the sample, there is a small chance that the result is difficult to interpret and additional testing, like amniocentesis, may be recommended.
What should I expect at my CVS appointment?
CVS is performed by a specialist in maternal-fetal medicine. You may need to travel to a dedicated hospital if this service is not available near you.
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 performed by a specialist in maternal-fetal medicine. You may need to travel to a dedicated hospital if this service is not available near you.
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.
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.
Authors: J Richer MD FCCMG FRCPC, S Morrison MS CGC, JE Allanson MD FRCPC, S Walji MD CCFP MPH, JC Carroll MD CCFP
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.
If looking to see if there is a cardiogenetics/cardiogenomics or cardiovascular specialty in your area, use the Ctrl +F function to search the page.
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
Authors: J Richer MD FCCMG FRCPC, S Morrison MS CGC, JE Allanson MD FRCPC, S Walji MD CCFP MPH, JC Carroll MD CCFP
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.
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…
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