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Untangling the Helix 2016: Genomics for primary care providers
Friday, November 11th, 2016
Vancouver, BC
2016 Family Medicine Forum
June C Carroll MD CCFP and Shawna Morrison MS CGC
Enclosed:
— Long QT syndrome GEC-KO on the run
— Familial hypercholesterolemia GEC-KO on the run
— Ethnicity-based carrier screening in Canada point of care tool
All handouts, presentation slide sets and additional point of care tools are available on www.geneticseducation.ca
LONG QT SYNDROME
Bottom line: Long QT syndrome (LQTS) is one of several inherited heart disorders than can lead to sudden cardiac
death (SCD). LQTS is a rhythm disorder that can predispose to fast, chaotic heartbeats which may trigger a sudden
fainting spell, seizure or SCD. It is treatable if diagnosed. The ECG is neither sensitive nor specific for hereditary
LQTS. A QTc ≥ 500ms is considered high risk for LQTS. Individuals with clinical features such as syncope, and
repeated corrected QT interval (QTc) of >450ms for men and >470ms for women, should be referred to a cardiac
arrhythmia specialist and a genetics clinic for assessment and genetic testing where indicated. Family physicians
can play a crucial role in referring first degree relatives to cardiac genetics specialist services following the death of
a young person in whom an autopsy did not identify cause of death or in whom a heritable cardiac disorder was
suspected.
WHAT IS LONG QT SYNDROME?
Long QT syndrome (LQTS) is a disorder involving the cardiac ion channels resulting in prolongation of the
ventricular action potential during cardiac repolarization (i.e. prolonged QT interval on electrocardiogram (ECG)). It
occurs in approximately 1 in 2,000 to 1 in 2,500 people. LQTS predisposes to syncope and/or sudden cardiac death
and is one of the leading causes of sudden death in otherwise healthy young people. LQTS is one of numerous
causes of sudden infant death syndrome (SIDS).
The diagnosis of LQTS usually relies on clinical and family history, in addition to a corrected QT interval (QTc).
Determination of an absolute value for an abnormal QTc is difficult as there is a considerable borderline range and
the data cut-offs are not clear. Acceptable cut-off values to balance a high positive predictive value and a lowered
false positive rate are shown in Table 1.
Table 1. Corrected QT interval (QTc) cut-offs which should prompt referral to cardiac arrhythmia specialists and
genetics clinic for assessment [Waddell-Smith et al, 2016 – see online for full reference].
Corrected QT interval cut-off (in ms)
Women
>470
Men
>450
Children >12 years
Female……………………………
Male ………………………………
>460
>450
Children <12 years (female
and male)
>450
In 20-40% of individuals the ECG may be inconclusive. Since a normal ECG cannot completely “rule out” LQTS, it is
recommended that patients be referred to a cardiac specialist for evaluation (which may involve manual
calculation of QTc and additional testing) if symptoms, signs or family history are present (Box 1).
www.geneticseducation.ca | @GECKOgenetics
Updated Aug 2016
Page 1 of 3
WHAT DO I NEED TO KNOW ABOUT THE GENETICS OF LONG QT SYNDROME?
Most forms of LQTS are hereditary, usually autosomal dominant. LQTS can also be acquired due to other causes
such as anorexia nervosa, or induced by certain medications (see Surveillance and Management).
At least 15 genes have been implicated in LQTS. Some genotype-phenotype correlations may be drawn. The three
most common genes, accounting for over 90% of known LQTS mutations, are:
— LQT1 (KCNQ1) on chromosome 11, which encodes potassium channel subunits
— LQT2 (HERG, KCNH2) on chromosome 7, which encodes potassium channel subunits
— LQT3 (SCN5A) on chromosome 3, which encodes sodium channel subunits
Box 1. Clinical symptoms, signs and family history which should prompt referral to cardiac arrhythmia specialists
and genetics clinic for assessment.
Syncope (loss of consciousness) or near syncope spells triggered by:
1. Physical exertion
2. Auditory stimuli e.g. fire alarm
3. Emotional stress/distress
— Repetitive events more concerning
— Excluding events that are likely due to vasovagal events is difficult but necessary (e.g.
those occurring during abrupt postural changes, exposure to heat and dehydration,
emotional reactions to events such as blood drawing, etc.)
Family history of unexplained sudden death in otherwise healthy persons at a young age (< 40
years)
— Attention to unexplained death during swimming, death during seizures, a family history
of "seizure" disorders and other unexplained deaths
o Sodium-channel abnormalities may be precipitated by fever. These cardiac events
may appear seizure-like and may be mislabelled as epilepsy.
Corrected QT interval of:
— Men: >450ms
— Women: >470ms
RED FLAGS TO CONSIDER GENETIC TESTING OR GENETIC CONSULTATION
Consider referral to your local genetics centre for:
Individuals with clinical symptoms (see Box 1) of LQTS or a suggestive ECG
First degree family members of individuals clinically diagnosed with LQTS
First degree relatives of an individual with a known mutation in a LQTS gene
Individuals with a family history of sudden death in a first degree relative under the age of 40
All of the above individuals should also be referred to a cardiac arrhythmia specialist.
SUDDEN ARRHYTHMIC DEATH IN THE YOUNG : OTHER DISORDERS
In addition to LQTS, there are other cardiac disorders, some of them heritable, which can cause sudden death in
young people. These include arrhythmogenic and hypertrophic cardiomyopathies, Brugada syndrome and
catecholaminergic polymorphic ventricular tachycardia (CPVT). Review of individuals who have experienced
cardiac arrest and their first degree relatives may identify a cause in up to~40% of cases. Family physicians may
play a crucial role in referring first degree relatives to cardiac genetics specialist services following the death of a
young person in whom autopsy did not identify cause of death or in whom a heritable cardiac disorder was
suspected. Please refer to Ellison (2015) for an overview of other inherited cardiac disorders that can cause SCD.
www.geneticseducation.ca | @GECKOgenetics
Updated Aug 2016
Page 2 of 3
WHAT DOES THE GENETIC TEST RESULT MEAN?
LQTS is autosomal dominant. A man or woman with LQTS due to a single faulty gene has a 50% chance of passing
the genetic risk for arrhythmia to each child.
LQTS demonstrates reduced penetrance (not every individual who inherits a mutation in a LQTS gene will develop
LQTS) and variable expressivity (clinical presentation can vary between affected individuals even within a family).
HOW WILL GENETIC TESTING HELP YOU AND YOUR PATIENT?
Genetic testing for LQTS can provide:
— Clarification of LQTS risk status for individuals with borderline clinical investigations
— Identification of individuals in whom a particular mutation confers a higher risk for SCD
— Assistance with life planning (e.g. decisions about careers, participation in competitive sports)
— Relief from worry, for those who test negative for a known family mutation, (a true negative result), as
they will not develop the disease in the future and know that their children are not at risk of inheriting the
disease
ARE THERE HARMS OR LIMITATIONS OF GENETIC TESTING?
Genetic testing can result in:
— Adverse psychological reaction, particularly due to potential for risk of sudden cardiac death, family
issues, distress
— Uncertainty due to a genetic variant of unknown significance
— Uncertainty due to limited sensitivity of genetic testing. About 1/4 of LQTS families do not have a
recognizable gene mutation
— Insurance/job discrimination
The perceived benefits and limitations of genetic testing may vary with an individual’s personal and family
experience of LQTS. The perspective of an individual who has lost a family member to LQTS contrasts significantly
with the perspective of an otherwise healthy individual whose prolonged QT interval was picked up incidentally on
routine ECG.
SURVEILLANCE AND MANAGEMENT
LQTS is treatable with beta-blockers, implantable cardioverter defibrillators, and avoidance of competitive sports,
electrolyte imbalances, and QT-prolonging medications [see www.crediblemeds.org for a comprehensive list (free
access, one-time registration required)].
Risk stratification takes into consideration factors such as QTc duration, genotype, gender and age.
For a recent review article on sudden cardiac death see Ellison S. Sudden cardiac death in adolescents. Prim Care
Clin Office Pract 2015: 42: 57–76. See online for complete reference list. Other LQTS resource: The Canadian
Sudden Arrhythmia Death Syndromes (SADS) Foundation website http://www.sads.ca/
Authors: C Honeywell MSc CCGC, J Rutberg MS CGC, R Gow MBBS FRACP, M Green MD FRCPC, JC Carroll MD
CCFP, JE Allanson MD FRCPC and S Morrison MS CGC
GEC-KO on the run is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO 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 judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of
information contained herein.
www.geneticseducation.ca | @GECKOgenetics
Updated Aug 2016
Page 3 of 3
FAMILIAL HYPERCHOLESTEROLEMIA
Bottom line: Familial hypercholesterolemia (FH) is a common (>1/500) autosomal dominant disorder that
results in a 20-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 ≥ 5mmol/L with additional
features such as 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 onset <45years, and family history of early
onset CVD or hyperlipidemia requiring treatment. Cascade screening of family members by genetic testing for
the familial gene mutation or LDL-C levels allows for early identification and treatment of at-risk individuals,
with statins as first-line treatment.
WHAT IS FAMILIAL HYPERCHOLESTEROLEMIA?
Familial hypercholesterolemia (FH) is a common autosomal dominant genetic condition where the uptake of lowdensity lipoprotein cholesterol (LDL-C) into cells is either decreased or inhibited. Most cases (80-90%) of FH are
caused by mutations in the LDL receptor gene LDLR. This results in lifetime exposure to very high levels of LDL-C.
FH results in a 20-fold increase in premature cardiovascular disease (CVD) and death in both men and women.
At least 1 in 500 Canadians is thought to have the heterozygous form of familial hypercholesterolemia (HeFH). FH
is more common in certain populations (e.g. 1/270 in French Canadians, 1/67 in Ashkenazi Jews) due to founder
effects.
Table 1. Clinical features of familial hypercholesterolemia in heterozygotes (HeFH) and homozygotes (HoFH).
Clinical features
HeFH
HoFH
Genetics
Mutation in one FH gene
LDL-C levels
≥ 5mmol/L with additional features shown in
following boxes
Mutation in both copies of an FH
gene
>12 mmol/L
Cardiovascular disease
onset
Physical findings
Family history
<55 years of age in men
<65 years of age in women
lower LDL-C levels, especially in
children or in treated patients, do
not exclude HoFH
<20 years of age (can be as early as
the first year of life)
— Cholesterol deposits in the tendons (xanthomata) and/or around the eyes
(xanthelasma)
— Arcus cornealis (white, grey, or blue opaque ring in the corneal margin) onset
<45years
— Early onset CVD
— Hyperlipidemia, often requiring treatment
HOW IS FAMILIAL HYPERCHOLESTEROLEMIA DIAGNOSED?
While there are no Canadian-specific FH diagnostic criteria, the Canadian Cardiovascular Society (CCS)
recommends using those published by the Dutch Lipid Clinic Network (see the FH Point of Care Tool).
Alternatively, criteria from the Simon Broome Registry can be used, and include lower thresholds for children with
suspected FH (Table 3). Both sets of diagnostic criteria are internationally accepted and used for diagnosis of FH,
although neither is designed to diagnose HoFH; in this case, other criteria have been suggested. See the FH Point of
Care Tool for more on diagnostic criteria.
Page 1 of 2
Updated Sept 2016
HOW TO RECOGNIZE INDIVIDUALS WITH FH:
An individual (>30years) with hypercholesterolemia (LDL-C ≥5mmol/L)
*
Exclusion of secondary causes of elevated LDL-C, e.g. obstructive liver disease, hypothyroidism,
nephrotic syndrome, anorexia nervosa
AND
Personal or family history of clinical stigmata of FH
OR
Personal or family history of premature CVD
OR
Family history of significant hypercholesterolemia, often requiring treatment
Individuals with LDL-C ≥5mmol/L and at least one of the features above are considered to have a possible FH
diagnosis. Those with LDL-C ≥ 5mmol/L and 2 additional features are considered to have a probable FH diagnosis.
CASCADE SCREENING
The most cost-effective approach for identification of new FH cases is cascade screening of family members of a
known index case (the first individual with a confirmed diagnosis). Screening can be by genetic testing for a known
familial gene mutation, LDL-C measurements or use of diagnostic criteria (See the FH Point of Care Tool). Some
experts recommend referral for specialist consultation beginning at age 2 years for those at high risk for HoFH
(individuals where both parents have HeFH).
WHERE DO I REFER MY PATIENT?
Find a Canadian FH specialist here.
You should refer your patient to your local genetics centre if s/he has had a positive genetic test result and would
like genetic counselling to discuss the implications for self and family. Include all relevant information on your
referral (e.g. family history, genetic test results, and investigations like LDL-C) to prevent unnecessary delays due to
further clarification needed before an appointment can be booked.
Note that genetics clinics vary with regard to the referrals they choose to accept. You may want to contact your
local centre for more information.
SURVEILLANCE AND MANAGEMENT
Statins are the drug class of choice for individuals with HeFH. LDL-C should be lowered as fast and as far as
possible. The CCS recommends a >50% reduction of LDL-C from baseline beginning at age 18 as primary
prevention with a goal of LDL-C <2.0mmol/L for secondary prevention. Some individuals with FH will require
combination and/or emerging therapy to obtain optimal LDL-C. Families with FH should be counselled about the
importance of lifestyle modification such as: smoking cessation and avoidance of passive smoking; diet; exercise;
daily activity beginning early in life; maintenance of ideal body weight; and stress reduction.
CHILDREN: Lifestyle modifications discussed above remain the cornerstone of CVD prevention in both children and
teens with FH and referral to a specialist for treatment decisions is recommended.
See www.geneticseducation.ca for the comprehensive GEC-KO Messenger with complete reference list and more
on HoFH, risks, benefits and limitations of genetic testing for FH. For Canadian screening, diagnosis and
management guidelines see Genest J, Hegele RA, Bergeron J, et al. Canadian Cardiovascular Society position
statement on familial hypercholesterolemia. Can J Cardiol 2014; 30(12): 1471-81.
Authors: S Morrison MS CGC, JE Allanson MD FRCPC, RA Hegele MD FRCPC, S Hadjiyannakis MD FRCPC and JC
Carroll MD CCFP
GEC-KO on the run is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO 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. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.
Page 2 of 2
Updated Sept 2016
Ethnicity-Based Screening in Canada
The Canadian Guidelines for Prenatal Diagnosis recommend preconception counselling and screening/testing for individuals belonging to population groups
1
known to have an increased risk for carrying certain genetic disorders (Tables 1 and 2) in order to arrange for prenatal testing if appropriate.
Table 1. Geographic distribution of ethnic populations at risk for hemoglobinopathies [reproduced from [2]].
It is recommended that all pregnant women from an ethnic background at increased risk of hemoglobinopathy and/or thalassemia (Table 1) be screened by
2
both CBC, to assess the MCV and MCH, and hemoglobin electrophoresis or high performance liquid chromatography (HPLC).
Regions of Origin
Thalassemia

Africa
Sickle Cell Disease (SCD)

SCD carrier frequency among African Americans is~ 810% and in many regions of Africa it is as high as 25-35%
Mediterranean region
e.g. Sardinia, Corsica, Sicily, Italy, Spain, Portugal, Greece, Cyprus, Turkey, Egypt, Algeria,
Libya, Tunisia, Morocco, Malta


Middle East
e.g. Iran, Iraq, Syria, Jordan, Saudi Arabia and other Arabian peninsula countries, Qatar,
Lebanon, Palestine, Israel (both Arabs and Sephardic Jews affected), Kuwait


South East Asia
e.g. India, Afghanistan, Pakistan, Indonesia, Bangladesh, Thailand, Myanmar

 in parts of India
Western Pacific region
e.g. Southern China, Vietnam, Philippines, Malaysia, Cambodia, Laos

Caribbean countries


South American countries


Note: Japanese, Koreans, Caucasians of Northern European ancestry, Native Americans (First Nations in Canada), and Inuit are not at increased risk of hemoglobinopathies.
www.geneticseducation.ca Update June 2014
2
Ethnicity-Based Screening in Canada
Table 2. Genetic disorders where a higher carrier frequency is found in individuals of a particular ancestry.
Disease
Carrier frequency in at-risk
population
Tay Sachs disease
3
1
Canavan disease
3
Familial dysautonomia
Cystic fibrosis
1
Ashkenazi Jewish (AJ) 1/30
Recommendation for offering carrier testing
French Canadians (FC) in
Eastern Quebec 1/14
DNA-based mutation analysis is recommended for:
 all at-risk couples
(where one individual of the couple is non-AJ or non-FC from Eastern Quebec, biochemical
testing can be considered)
Ashkenazi Jewish 1/37-57
Ashkenazi Jewish 1/32
DNA-based mutation analysis is recommended for:
 all at-risk couples
Northern European 1/25-30
Ashkenazi Jewish 1/24
DNA-based mutation analysis is recommended for:
 Individuals with a family history of CF (and their partners)
 Both parents of a fetus with an ultrasound diagnosis of echogenic bowel
Canadian College of Medical Geneticists does not recommend carrier testing for the general
population at this time.
NOTE: Genetic testing for conditions more often seen in Ashkenazi Jewish ancestry is frequently offered as a panel. Contact your contact your local genetics
centre for more information.
Contact your local genetics centre to learn more about the community you serve and if there is an at-risk population you should be considering for referral for
genetic consultation (e.g. individuals from Saguenay-Lac-St-Jean/Charlevoix regions of Quebec).
www.geneticseducation.ca Update June 2014
References
[1] Chodirker BN, Cadrin C, Davies GAL et al. Canadian guidelines for prenatal diagnosis. Genetic indications for prenatal diagnosis. SOGC Clinical Practice
Guideline No. 105, June 2001. J Obstet Gynaecol Can 2001;23:525–31
[2] Langlois S, Ford JC, Chitayat D et al. Carrier screening for thalassemia and hemoglobinopathies in Canada. SOGC Clinical Practice Guideline No. 218, October
2008. J Obstet Gynaecol Can 2008; 30(10): 950-971
[3] Langlois S, Wilson RD, Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. Prenatal Diagnosis Committee of the
Canadian College of Medical Geneticists Carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent. J Obstet Gynaecol
Can 2006; 28(4):324–43