Medical Genetics

Question 1

Case 1: A family history of sudden death

Patient SL is a 22 year old female that initially presented at consultation for dyspnoea, palpitations and chest pain.

Her family history revealed that her maternal grand-father died suddenly at 41years, and believed to caused by a cardiac arrhythmia.

In addition, a maternal cousin, a professional footballer also died suddenly at age 26 during a training session.

A few other family members seem to have been consulted for heart issues.

What is the most likely mode of inheritance?

What is the most likely diagnosis?

What roles can a medical geneticist play for this family?

Answer 1

Most Likely Mode of Inheritance: Autosomal dominant.

Most Likely Diagnosis: Hypertrophic Cardiomyopathy (HCM), due to the family history of sudden death and related cardiac symptoms.

Role of a Medical Geneticist:
Provide genetic counseling.
Facilitate genetic testing for family members.
Assess risk and recommend screening.
Collaborate on management plans with cardiologists.
Offer family planning options to prevent passing on the condition.

Question 2

Familial sudden death

Answer 2

Think of

HOCM

Inherited rhythm disturbance

NB long QT syndromes / ARVC

Vascular rupture “connective tissue”

NB Marfan syndrome

Question 3

Cardiomyopathy

Answer 3

A myocardial disorder in which the heart muscle is structurally and functionally abnormal,

in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality

Question 4

Types of cardiomyopathy

Answer 4

Hypertrophic CM
Restrictive CM
Dilated CM

Question 5

Define HCM

Answer 5

increased ventricular wall thickness in the absence of loading conditions

Question 6

Define DCM

Answer 6

DCM – LV dilatation and LV systolic dysfunction in absence of loading conditions or coronary artery disease

Question 7

Restrictive CM

Answer 7

Restrictive CMO – restrictive ventricular physiology with normal/ diastolic volume and normal/ systolic volumes with normal ventricular thickness

Question 8

What is Hypertrophic Cardiomyopathy (HCM)?

Answer 8

HCM is defined as increased ventricular wall thickness in the absence of loading conditions, such as hypertension or aortic stenosis.

Question 9

What is Dilated Cardiomyopathy (DCM)?

Answer 9

DCM is characterized by left ventricular (LV) dilatation and LV systolic dysfunction in the absence of loading conditions (e.g., hypertension) or coronary artery disease.

Question 10

What is Restrictive Cardiomyopathy (RCM)?

Answer 10

RCM is defined by restrictive ventricular physiology with normal or reduced diastolic volume, normal or reduced systolic volume, and normal ventricular wall thickness.

Question 11

What is Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)?

Answer 11

ARVC is a condition where there is progressive replacement of right ventricular myocardium by adipose (fat) or fibrotic tissue.

Question 12

What percentage of familial Hypertrophic Cardiomyopathy (HCM) cases have an increased risk of Sudden Cardiac Death (SCD)?

Answer 12

10-20% of familial HCM cases have an increased risk of SCD.

Question 13

What proportion of athlete deaths in the USA are caused by Hypertrophic Cardiomyopathy (HCM)?

Answer 13

HCM is responsible for 1/3 of sudden cardiac deaths in athletes in the USA.

Question 14

In which age group is Sudden Cardiac Death (SCD) most common due to Hypertrophic Cardiomyopathy (HCM)?

Answer 14

SCD due to HCM most often occurs in adolescents or young adults.

Question 15

Can Sudden Cardiac Death (SCD) be the first manifestation of Hypertrophic Cardiomyopathy (HCM)?

Answer 15

Yes, SCD may be the first manifestation of HCM.

Question 16

What is the general population risk of Sudden Cardiac Death (SCD) in individuals with Hypertrophic Cardiomyopathy (HCM)?

Answer 16

In the general population with HCM, the risk of SCD is 1%.

Question 17

screening for relatives

Answer 17

Autosomal dominant / High penetrance

History, examination, ECG, echo.

Genetic testing only if mutation known

If normal – annual from 12-18 yrs, then 3-5yrly

Question 18

How many genes are involved in genetic testing for conditions like Hypertrophic Cardiomyopathy (HCM)?

Answer 18

At least 24 genes are involved in genetic testing for HCM and related conditions.

Question 19

What is the cost of sequencing individual genes in genetic testing?

Answer 19

Sequencing individual genes costs approximately 600-900 euros per gene.

Question 20

What is “panel testing” in genetic testing, and how much does it cost?

Answer 20

“Panel testing” involves sequencing 3 or 4 genes at a time and typically costs around 1500 euros.

Question 21

What are some challenges of exome sequencing in genetic testing?

Answer 21

Exome sequencing generates a large amount of data, may involve unknown genes, and can lead to Variants of Uncertain Significance (VOUS), which are genetic variants with unclear implications.

Question 22

Case 2: Infertility in an Afrikaner Couple

Mr and Mrs J presented for assessment of primary infertility. Mr J (age 33yrs) was found during that work up to have congenital bilateral absence of the vas deferens.

This diagnosis is classically associated with abnormalities of CFTR so Mr J underwent molecular analysis of the CFTR gene using a multiplex 30 mutation analysis kit.

His results showed the presence of the deltaF508 mutation and the 3272-26 A>G mutation.

Why is the ancestry background important?

Which are common features of cystic fibrosis?

Mr J’s sister is pregnant with a girl. Her partner is Italian (population carrier frequency 1 in 20) and has no family history of CF. The risk for this baby to have CF?

Knowing the mutations in CF is useful, because?

Answer 22

Q: Why is ancestry background important in this case?
A: Ancestry is important because certain populations, like Afrikaners, have a higher carrier frequency of specific genetic mutations, such as those in the CFTR gene, which can be associated with conditions like cystic fibrosis (CF). Population-specific mutations may help guide genetic testing and risk assessment.

Q: What are common features of cystic fibrosis (CF)?
A: Common features of CF include:
- Chronic respiratory infections
- Pancreatic insufficiency
- Elevated sweat chloride levels
- Male infertility due to congenital bilateral absence of the vas deferens (CBAVD)
- Malabsorption and poor growth
- Liver disease

Question 23

What are the typical clinical features of cystic fibrosis (CF)?

Answer 23

Typical clinical features of CF include:

Chronic lung infections and bronchiectasis
Pancreatic insufficiency
Meconium ileus in newborns
Elevated sweat chloride levels
Male infertility due to congenital bilateral absence of the vas deferens (CBAVD)
Failure to thrive and malnutrition

Question 24

What are some atypical presentations of cystic fibrosis (CF)?

Answer 24

Atypical presentations of CF may include:

Isolated male infertility (CBAVD) without respiratory or pancreatic symptoms
Mild lung disease with normal or borderline sweat chloride levels
Single-organ involvement, such as chronic sinusitis or pancreatitis

Question 25

What are the indications for molecular genetic testing in cystic fibrosis (CF)?

Answer 25

Indications for molecular genetic testing include:

Confirming a diagnosis of CF in symptomatic individuals
Carrier testing in individuals with a family history of CF
Screening in at-risk populations based on ethnic background
Reproductive counseling and prenatal diagnosis

Question 26

What are the limitations of molecular genetic testing in cystic fibrosis (CF)?

Answer 26

Limitations include:

Not all CFTR mutations may be detected by standard panels, especially rare mutations
Variants of Uncertain Significance (VOUS) may complicate interpretation
Ethnic-based testing may miss mutations common in other populations

Question 27

Why is ethnic-based genetic testing important for cystic fibrosis (CF)?

Answer 27

Ethnic-based testing is important because certain CFTR mutations are more common in specific populations. For example, deltaF508 is common in Caucasians, while other mutations may be prevalent in different ethnic groups, affecting test selection and accuracy.

Question 28

What are the familial and reproductive implications of genetic disorders like cystic fibrosis (CF)?

Answer 28

In CF, carriers can pass the mutation to offspring, and if both parents are carriers, there’s a 25% chance the child will have CF. Family members may also need carrier testing. Infertility is a common issue, particularly in men with CF due to CBAVD.

Question 29

What is risk assessment in the context of cystic fibrosis (CF)?

Answer 29

Risk assessment involves calculating the probability of being a carrier or passing CF to offspring, based on family history, carrier status, and ethnic background. It helps guide genetic counseling and reproductive decisions.

Question 30

How does genotype-phenotype correlation apply to cystic fibrosis (CF)?

Answer 30

Genotype-phenotype correlation in CF refers to the relationship between specific CFTR mutations and the severity of the disease. Some mutations lead to classic CF with multi-organ involvement, while others may result in milder, atypical forms of CF.

Question 31

What is gene-directed therapy in cystic fibrosis (CF)?

Answer 31

Gene-directed therapy targets specific CFTR mutations to improve or restore function. For example, CFTR modulators, such as ivacaftor and lumacaftor, are designed to treat individuals with certain CF mutations by correcting the underlying protein defect.

Question 32

What are CFTR-related phenotypes, and how do they differ from cystic fibrosis (CF)?

Answer 32

CFTR-related phenotypes include conditions like Congenital Absence of the Vas Deferens (CAVD), where individuals have mutations in the CFTR gene but do not present with the full spectrum of CF symptoms. These individuals may have isolated symptoms like infertility.

Question 33

What is Congenital Absence of the Vas Deferens (CAVD)?

Answer 33

CAVD is a condition where the vas deferens, a key structure for sperm transport, is absent, leading to male infertility. It is commonly associated with mutations in the CFTR gene, but individuals may not have other cystic fibrosis symptoms.

Question 34

What is clinical validity in genetic testing?

Answer 34

Clinical validity defines the ability of a genetic test to detect or predict the presence of a specific phenotype (i.e., the manifestation of a disease or disorder). It reflects how well the test results correlate with the clinical presentation of the condition

Question 35

What is analytic validity in genetic testing?

Answer 35

Analytic validity refers to the accuracy of a test in identifying the presence or absence of a specific genetic variant in a defined setting. It measures the technical performance of the test, including its sensitivity, specificity, and reproducibility.

Question 36

G6PD deficiency is common in African, Mediterranean, and Asiatic populations in which malaria has been endemic. Multiple different mutations have been found in different populations.

This high frequency of G6PD mutations is best explained by:

A. Genetic drift
B. The influence of drugs that cause hemolytic anemia
C. Balanced polymorphism
D. Founder effect

Answer 36

C. Balanced polymorphism

Feedback:
The high frequency of G6PD mutations in areas in which malaria is endemic is an example of a balanced polymorphism. The mutation is maintained in the population at this high frequency because of the protective advantage of heterozygosity.

Question 37

A large percentage of individuals with a1-antitrypsin deficiency will develop chronic obstructive pulmonary disease (COPD) or emphysema.

The severity of this disease will be significantly increased if the patient is:

A. a woman
B. homozygous for null alleles of the elastase gene
C. heterozygous for the mutation, with one normal copy of the a1-antitrypsin gene
D. a cigarette smoker

Answer 37

D. a cigarette smoker

About 80% of individuals homozygous for the Z allele of the Pi (protease inhibitor) locus develop pulmonary emphysema. This observation lends support to the protease-antiprotease theory of emphysema, which holds that emphysema results from an imbalance between proteases like neutrophil elastase and protease inhibitors like a1-antitrypsin in the lung. The Pi locus codes for the a1-antitrypsin protein, which is produced predominantly in the liver and secreted into the serum. The Z allele results in defective transport of the a1-antitrypsin protein from the endoplasmic reticulum to the Golgi apparatus and consequent reduced serum concentrations. PiZZ homozygotes have serum a1-antitrypsin levels that are about 10% of normal.

Pulmonary emphysema in these patients occurs with greater severity and at an earlier age if the patient is a smoker. The protease-antiprotease theory of emphysema can explain the tendency of even normal smokers to develop emphysema, since cigarette smoke both increases the amount of protease in the lung and decreases the activity of a1-antitrypsin. In PiZZ individuals this effect is magnified.

Having one normal copy of the a1-antitrypsin gene, having a deficiency of elastase, or being neutropenic would all be expected to reduce the severity of emphysema in PiZZ individuals.

Question 38

The ______ is the set of observable characteristics and is the sum of genetic and environmental effects.

Answer 38

phenotype

Question 39

Mitochondrial pattern on inheritance

Answer 39

Feedback:
Mitochondrial inheritance. Why? Matrilinear inheritance: both males and females are affected, but affected children can only arise from an affected mother. Affected males have unaffected children, and all children of affected women are affected.

Question 40

Two parents with autosomal recessive albinism have a child who does not have albinism. This is best explained by:

A. Misattributed paternity
B. Genetic heterogeneity
C. Reversion of one of the mutant alleles to wild type
D. An incorrect diagnosis in one parent

Answer 40

B. Genetic heterogeneity

Feedback:
Any of these explanations might be possible, but the most likely is genetic heterogeneity. There are several forms of albinism due to mutations in distinct genes. A child of two parents affected with different gene mutations would be heterozygous for both, but would be unaffected.

Question 41

Which of the following conditions is caused by a trinucleotide (triplet) repeat expansion?

A. Cystic fibrosis
B. Duchenne muscular dystrophy
C. Huntington disease
D. Osteogenesis imperfecta

Answer 41

C. Huntington disease

Huntington disease is caused by expansion of a CAG repeat. The most common mutation in cystic fibrosis and Duchenne muscular dystrophy is a deletion. Most cases of osteogenesis imperfecta are caused by point mutations or deletions in one of the collagen genes.

Question 42

Which is NOT a typical mechanism by which a proto-oncogene is converted to an oncogene?

A. A chromosomal translocation resulting in the up-regulation of the proto-oncogene
B. Complete deletion of the proto-oncogene
C. Amplification of the proto-oncogene
D. A point mutation in the proto-oncogene

Answer 42

B. Complete deletion of the proto-oncogene

Feedback:

All of these answers may result in the conversion of a proto-oncogene to an oncogene except for complete deletion of the proto-oncogene. Deletion of the proto-oncogene would not be expected to lead to cancer. Deletion of tumour suppressor genes, in contrast, is a step in the progression of many lesions to cancer; for example, a germline deletion of the RB gene leads to familial retinoblastoma.

Amplification of the N-myc proto-oncogene is seen in some neuroblastomas; chromosomal translocations lead to the up-regulation of the myc gene in Burkitt’s lymphoma; and a point mutation in codon 12 of the ras gene can lead to a constitutively active protein product.

Question 43

In DNA, adenine normally pairs with:

A. uracil
B. thymine
C. cytosine
D. guanine

Answer 43

B. thymine

Feedback:
Adenine pairs with uracil in RNA and with thymine in DNA.

Question 44

Which of the following karyotypes is not compatible with survival to birth?

A. 47,XY,+13
B. 47,XY,+21
C. 47,XX,+18
D. 45,Y

Answer 44

D. 45,Y

Feedback:
The human embryo cannot survive without an X chromosome.

Question 45

A child is born with a cleft lip and palate.

This birth defect may be associated with the following:

A. A chromosome disorder such as trisomy 13
B. A disruption defect related to amniotic bands
C.
A healthy, otherwise completely normal, newborn infant
D. All of the answers are correct
E. Only A and C above are correct

Answer 45

D. All of the answers are correct

Cleft lip and palate can be isolated birth defects or features of a larger clinical picture.

Question 46

Approximately what percentage of all pregnancies result in the birth of a child with a significant genetic disease or birth defect that can cause crippling, mental retardation, or early death?

A. 25%
B.
0.1%
C. 0.01%
D. 3%

Answer 46

D. 3%

Genetic diseases are not at all rare. Though there are many rare genetic diseases, in aggregate they are a significant cause of morbidity and mortality. About 3% of pregnancies result in the birth of a child with a significant genetic disease or birth defect that can cause crippling, mental retardation, or early death.

Question 47

Genetic counselling includes all of the following EXCEPT:

A. Discussion of available therapies
B. Recommendation of specific reproductive options
C.
Discussion of the impact of the disease on the patient and family
D. Discussion of available genetic testing
E.
Assessment of the occurrence or recurrence risk

Answer 47

B. Recommendation of specific reproductive options

Question 48

A young woman of northern European descent is the single parent of a child with autosomal recessive cystic fibrosis. She marries her first cousin and becomes pregnant.

What is the probability that her child will have cystic fibrosis?

A. 1/2500
B. 1/100
C. 1/32
D. 1/4

Answer 48

C. 1/32

Feedback:
To work this problem draw out the family lineage, calculate the risk of having the CF gene at each branch and multiply each risk. The parent of this woman through whom she is related to her first cousin has a 1/2 chance of carrying the mutant CF, this parental sib has a 1/2 chance of carrying the allele and this person’s child (the first cousin) also has a 1/2 chance of carrying the mutant allele. Cumulative risk = 1/2 x 1/2 x 1/2 = 1/8 that the first cousin has a mutant allele. Then the risk to have an affected child is 1 x 1/2 x 1/8 x 1/2 = 1/32.

Question 49

Which of the following findings on prenatal ultrasound examination would not raise suspicion of a chromosome abnormality?

A. Holoprosencephaly
B. Monozygotic twins
C. Duodenal atresia
D. Hydrops fetalis

Answer 49

B. Monozygotic twins

Question 50

A dominantly inherited trait affects a child and his grandmother, but neither parent. This best illustrates which of the following principles?

A. New mutation
B. Somatic mosaicism
C. Variable expressivity
D. Non-penetrance

Answer 50

D. Non-penetrance

Feedback:
A skipped generation for a dominant trait is an example of non-penetrance. Variable expressivity would result in different levels of expression in different individuals who carry the gene. Somatic mosaicism would not occur in the child’s parent, since the parent who inherited the trait from the grandmother would have the mutation in all cells.

Question 51

Myotonic dystrophy may show increasing severity and earlier age of onset in successive generations.

This phenomenon is known as:

A. Incomplete penetrance
B. Locus heterogeneity
C. Variable expressivity
D. Anticipation

Answer 51

D. Anticipation

Feedback:
Anticipation may be defined as “increasing severity and earlier age of onset in successive generations”. Anticipation is most often due to the gradual expansion of a trinucleotide repeat element in the gene whose mutation causes the disease. Myotonic muscular dystrophy is caused by the expansion of a GCT repeat in the 3’ untranslated region of the gene. Normal individuals have 5-35 copies of the repeat, while patients with MMD always have greater than 50 copies, and some patients have greater than 1000 copies. Expansion of these trinucleotide repeats occurs primarily when the gene goes through female meiosis. In fact, congenital MMD, caused by trinucleotide expansions containing thousands of copies, is caused only by alleles that are inherited maternally.

Other genetic disorders caused by the expansion of trinucleotide repeats include fragile X syndrome and Huntington disease.

Question 52

Haemophilia A and haemophilia B have nearly identical phenotypes, but they result from mutations in different genes on the X chromosome.

This is an example of:

A. Double heterozygosity
B. Variable expressivity
C. Locus heterogeneity
D. Compound heterozygosity

Answer 52

C. Locus heterogeneity

Feedback:
Locus heterogeneity refers to mutations at different genetic loci (genes) that can cause the same or a similar phenotype. This situation fits the definition perfectly, since mutations at either of two loci on the X chromosome can both cause the haemophiliac phenotype.

Question 53

Cystic fibrosis mutation consists of ….

A. a duplication
B. an insertion
C. a substitution
D. a deletion

Answer 53

D. a deletion

Question 54

If both parents are affected with the same autosomal recessive disorder then the probability that each of their children will be affected equals ___.

A. 2 in 3
B. 1 in 4
C. 1
D. 1 in 2

Answer 54

C. 1

Feedback:
If both parents are affected then they will both transmit a mutant allele to all of their children who will all therefore be affected.