Genetics

Question 1

Common single gene conditions (7)

Answer 1

1. Hereditary haemochromatosis (1 in 300)
2. Familial hypercholesterolaemia (1 in 500)
3. BRCA1/2 (1 in 1000)
4. Alpha-1-antitrypsin deficiency (1 in 1700)
5. HNPCC (1 in 2000)
6. Cystic fibrosis (1 in 3000)
7. Neurofibromatosis (1 in 3000)

Question 2

Autosomal dominant inheritance

Answer 2

1. No difference whether you are male or
   female
2. A 50/50 chance that a child will inherit
3. There may be incomplete penetrance, variable expressivity
4. A single affected person in a family may have a ‘de-novo’ AD mutation in a gene

Question 3

Autosomal recessive inheritance

Answer 3

1. No difference whether male or female
2. Both parents must carry mutation for children to be at risk
3. In that situation each child has a 1 in 4 chance of inheriting the disease
4. Usually only one generation in a family is at risk. [Exceptions: highly consanguineous families or high gene frequencies in the general population]

Question 4

Autosomal recessive disorders (11)

Answer 4

1. Deafness
2. Albinism
3. Wilson disease
4. Sickle cell disease
5. Thalassaemia
6. Cystic fibrosis
7. Homocystinuria
8. Friedreich ataxia
9. Phenylketonuria (PKU)
10. Haemochromatosis
11. Alpha-1-antitrypsin deficiency

Question 5

X-linked inheritance

Answer 5

1. Affected males linked by unaffected females (x-linked dominant can mean female shows phenotype, or skewed x-inactivation)
2. No male to male transmission

Question 6

X-linked recessive disorders (9)

Answer 6

1. Haemophilia A
2. G6PD deficiency
3. Fabry disease
4. Ocular albinism
5. Testicular feminization
6. Chronic granulomatous disease
7. Fragile X syndrome
8. Colour blindness
9. Duchenne and Becker muscular dystrophy

Question 7

X-linked dominant disorders (3)

Answer 7

1. Vitamin D resistant rickets
2. Rett syndrome
3. Incontinentia Pigmenti

Question 8

Polygenic inheritance

Answer 8

Threshold for disease needs to be met with many genes playing an additive role

1. These conditions cluster in families but do not follow predictable inheritance patterns.
2. Environmental factors also often contribute to disease development

Question 9

Klinefelter syndrome

Answer 9

47XXY
 Tall stature
 Infertility
 Low testosterone
 Mild learning difficulties

Question 10

Turner syndrome

Answer 10

45X0
 Short stature
 Ovarian dysgenesis
 Infertility
 Heart and renal defects
 Normal intellect

Question 11

Robertsonian translocation

Answer 11

Afrocentric chromosomes (13, 15, 15, 21, 22) - don’t have a p arm and thus with two q arms can lead to trisomy in offspring

Question 12

Prader-Willi syndrome (and…)

Answer 12

Absence of paternally functioning genes
- 70% paternally derived deletion of 15q12
- 25% maternal uniparental disomy 15
- <1% imprinting defect

Angelman - absence of maternally functioning genes

Question 13

Trinucleotide expansions (5)

Answer 13

Features = intergenerational instability, anticipation, permutations, genotype-phenotype correlation

1. Fragile X syndrome
2. Friedrich Ataxia
3. Huntington
4. Spinocerebellar ataxia
5. Myotonic dystrophy

Question 14

Myotonic dystrophy

Answer 14

 Muscle Weakness / Cataract / Myotonia / Infertility
 CTG Repeat
<37- No Problem
>50- Disease
50-100- Generally Mild
Congenital Form Often >1000
 Congenital Form Almost Always Maternally Inherited
 Worse With Succeeding Generations (Anticipation)

Question 15

fragile X syndrome

Answer 15

 CGG Repeat
 <50- Normal and No Risk for Offspring
 50-200= ‘Premutation’- shy, 20% premature ovarian failure, risk to Offspring of Females, in males ataxia, tremor FAXTAS
 >200 = ‘Full mutation’- Males have intellectual disability but intellect in females is variably affected (50% intellectual disability)

Question 16

Huntington Disease 1

Answer 16

 1:10 000, autosomal dominant neurodegeneration
 Chorea, Cognitive impairment, Psychiatric/ personality changes
 CAG Repeat&raquo_space; Polyglutamine
 Intergenerational instability
- Male > Female Transmission
- Juvenile Onset HD Almost Always Paternally Inherited
- Repeats >29 Unstable
- 36-39 = reduced penetrance
- 40+ = huntigton
 Protein = Huntingtin- Unknown Function
 Likely That Expansion Confers A Toxic Gain Of Function
 Onset > death = 15 years

Question 17

Mitochondrial inheritance + unique features

Answer 17

1. Affected mothers pass on the mutation to all children (though mutant loads may vary)
2. Males cannot pass on the disorder
3. Variable expressivity is common

Unique features
- heteroplasty = coexistence of mutant & wt
- bottleneck = small number of genomes selected to repopulate oocyte
- threshold effect = critical number of mutant DNA needed for each tissue to become dysfunctional

Question 18

Mitochondrial diseases (7)

Answer 18

1. MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes)
2. MERRF (Myoclonic Epilepsy with Ragged Red Fibres)
3. Leber Hereditary Optic Neuropathy (LHON)
4. External Ophthalmoplegia
5. Kearns-Sayre syndrome
6. Chronic progressive external ophthalmoplegia
7. NARP (Neurogenic weakness Ataxia with Retinitis Pigmentosa)

Question 19

A single nucleotide polymorphism (SNP) with 2 alleles, A and B, has been shown to be associated with an increased risk of celiac disease in homozygotes of allele B.
In the general population, 36% of the population is homozygous for allele A. In the same population, what proportion of the population is at increased risk of celiac disease as a result of homozygosity for allele B?

A. 6%
B. 16%
C. 36%
D. 64%

Answer 19

Hardy-Weinberg
1 = p2 + 2pq + q2
where p is and q are frequencies of alleles

B

Question 20

Melanie has 2 brothers affected with Duchenne muscular dystrophy. Melanie’s daughter is pregnant. What is the risk to Melanie’s grandchild of developing DMD?
A.1 in 2
B.1 in 4
C.1 in 16
D.1 in 32

Answer 20

C. 1 in 16

Question 21

John and Rita are having their first child together. They are unrelated. John’s niece and Rita’s brother both had cystic fibrosis.
What is the risk to their child of developing cystic fibrosis?
A. 1 in 36
B. 1 in 18
C. 1 in 16
D. 1 in 12

Answer 21

D. 1 in 12

Question 22

Bill and Cindy are planning to have a child and are concerned about having a child with phenylketonuria (PKU). Bill had a son with a previous partner that died from PKU. Cindy has no family history of PKU. The couple are non-consanguineous. The carrier frequency of PKU in the general population is 1 in 50.
What is the risk of the couple having a child affected with PKU?
A.1⁄4
C.1/100
D.1/200
E. 1/300

Answer 22

D.1/200

Question 23

A recessive condition is known to have a carrier frequency of 1/8 in the community. What is the likelihood that a couple with unknown carrier status will have an affected child?
A) 1/32
B) 1/64
C) 1/128
D) 1/256

Answer 23

D) 1/256

Question 24

Familial cancer syndromes and genes associated (4)

Answer 24

1. Hereditary Non-polyposis Colorectal Cancer
   (HNPCC) - MLH1/MSH2/MSH6
2. Familial Adenomatous Polyposis (FAP) - APC
3. Hereditary Breast/Ovarian Cancer - BRCA1, BRCA2
4. Neurofibromatosis type 1 - NF1

Question 25

Rarer familial cancer syndromes

Answer 25

1. Neurofibromatosis type 2 = NF2
2. Li-Fraumeni syndrome = p53
3. MEN1
4. MEN2A, 2B, Familial Medullary Thyroid Cancer = RET
5. Retinoblastoma = RB1
6. Von Hippel-Lindau syndrome
7. Basal cell naevus syndrome (Gorlin syndrome) = PTCH
8. Cowden syndrome = PTEN
9. Familial melanoma = P16
10. Hereditary Diffuse Gastric Cancer = CDH1
11. Autosomal recessive colorectal adenomatous polyposis = MUTYH (MYH)

Question 26

Hereditary Non-Polyposis Colorectal
Cancer

Answer 26

Main features:
- Autosomal dominant in DNA mismatch repair: most often MLH1, MSH2, MSH6 (Most families have unique mutations) resulting in microsatellite instability
- Tumour suppressor genes thus accelerated transformation of normal polyps to colon cancer

Lifetime cancers risks:
- Colorectal Ca ~80%, median age 44 years, 2/3rds ‘right’ sided
- Endometrial Ca ~40%
- Ovarian Ca ~10%
- Gastric, small intestine, renal pelvis/ureter, pancreatic, gliomas (Turcot syndrome), hepatobiliary - each < 10%

Diagnosis
- family history most sensitive
- microsatellite instability - 90% in HNPCC while 10% in sporadic
- tumor IHC for mismatch repair

Question 27

Familial Adenomatous Polyposis

Answer 27

• Autosomal dominant, mutations in APC gene (Most unique family mutations, 95% are truncating mutations)
• 10% have ‘attenuated FAP’ with later onset (more right sided)

Clinical features
- Onset of polyposis 12-25 years - 100% risk (most left sided)
- Extra-colonic features:
1. Gastric and duodenal polyposis/cancer-potential cause of mortality post- colectomy
2. Bone cysts (especially in jaw; previously called Gardener syndrome)
3. Desmoid tumours
4. Low risk of other cancers: medulloblastoma, biliary tract, thyroid, hepatoblastoma

Diagnosis = colonoscopy followed by genetic testing

Management - total colectomy with ilioanal pouch as teen, endoscopy 2 yearly

Question 28

BRCA1 & BRCA2

Answer 28

• Increased risk of ovarian cancer: BRCA1 20-40%, BRCA2 2-20%
• BRCA2: risk of male breast cancer, small increased risk of prostate ca.
• Increased in the Ashkenazi Jewish population

Management
- mammogram from 30yo
- ovarian US from 35yo
- prophylactic mastectomy reduces risk by 90% (sapling-oophorectomy - less research but similar)

Question 29

Gaucher disease - gene + features (5)

Answer 29

Autosomal recessive mutation of GBA1 leading to accumulation of glucocerbrosidases lipids

Features
- Hepatosplenomegaly may be asymptomatic or may be associated with early satiety, abdominal complaints (distension, discomfort, pain), and/or anaemia and thrombocytopaenia.
- Bone/ joint pain - Erlenmeyer flask deformity
- ILD
- Neurocognitive
- Associated with Parkinson disease

Question 30

Hemophagocytic lymphohistiocytosis - what is it, triggers, findings

Answer 30

Life-threatening, hyper-inflammatory disorder via CD8 and NK cells

Triggers: autoimmune disorder, infection, malignancy, familial presents in newborn

Features
- fever
- cytopenias
- splenomegaly
- hypertriglyceridemia
- ferritin >500
- elevated sIL2Ra

Treat with immunosuppression followed by BM transplant

Question 31

The genetics of complex diseases involves not a single gene mutation but multiple genes and
their interaction with environmental factors. Which of the following is true?
a. Twin studies are of little value in complex genetic disorders
b. ERAP-1 allele deletion is protective for Ankylosing spondylitis
c. Ulcerative Colitis is associated with NOD-2 allele
d. Genome wide association studies failed to identify risk loci for Schizophrenia
e. Heavy cannabis use has a causal role in the development of Schizophrenia

Answer 31

Answer: B
The development of Genome wide association studies (GWAS) has resulted in the identification of
risk alleles in a number of complex diseases with a strong familial risk.

Twin studies -especially in diseases with a strong familial tendency have been invaluable in identifying conditions where multiple genetic mutations are likely and where an environmental factor is also likely. Such diseases include, Type-1 diabetes, inflammatory bowel disease, ankylosing spondylitis and schizophrenia.

In Ankylosing spondylitis a functional ERAP-1 protein is necessary to present peptides to HLA-B27.
Individuals who are HLA-B27 positive but lack ERAP-1 are protected against the disease.

NOD-2 is a gene that is specifically associated with distal ileal Crohn’s Disease and thus identifies a specific subset of patients with this condition.

Schizophrenia has a familial predisposition in some
presentations.

Whilst cannabis use appears to precipitate or worsen schizophrenia on some individuals, it is not a universal environmental trigger and so is not strictly causal.