Genetics

Question 1

Gene mutation causing CHARGE syndrome

Answer 1

CHD7 gene

Question 2

Features of Prader Willi syndrome?

Answer 2

Hyperphagia
Obesity
Short stature
Hypotonia
Hypogonadism
Mental retardation

Question 3

Features of Angelman syndrome

Answer 3

Mental retardation
Seizures
Frequent smiling and laughing
Growth retardation

Question 4

Genetic cause of Angelman syndrome?

Answer 4

15q12 is usually paternally imprinted (silence)
Disease when maternal copy of 15q12 is deleted (70%) paternal uniparental disomy (2%) or point mutation in the functional copy of UBE3A gene

Question 5

Genetic cause of Prader Willi Syndrome

Answer 5

Maternal imprinting (silencing)

70% have deletion of the paternally derived 15q11-12
25% have maternal uniparental disomy

Question 6

Pedigree rules for imprinting?

Answer 6

• Sex of the transmitting parent will always be the same across the pedigree (eg always a transmitting male)

Question 7

Examples of triplet repeat expansion disorders?

Answer 7

Fragile X: CGG
Myotonic dystrophy: CTG
Friedreichs Ataxia: GAA (the only recessive one)
Huntingtons: CAG

Question 8

What is the concept of ‘anticipation’ in genetics?

Answer 8

Applies to triplet repeat expansion disorders: earlier onset in subsequent generations

Question 9

Features of Freidreich’s Ataxia

Answer 9

Early loss of vibration sense and proprioception
Ataxia of all 4 limbs
Hypo/arreflexia
Weakness (LL then UL)
Cerebellar dysarthria

Question 10

What 3 features may be seen with fragile X pre mutation (50-200 CGG repeats)?

Answer 10

1. Premature ovarian failure
2. Fragile X tremor-ataxia syndrome
3. Neurocognitive defects later in life

Question 11

Risk of recurrence with gonadal mosaicism?

Answer 11

Usually low risk e.g. 1-2-3%

Question 12

Which conditions increase with consanguinity?

Answer 12

Autosomal recessive

Question 13

Examples of X-linked dominant conditions?

Answer 13

Incontinentia pigmenti
Rett syndrome
X-linked hypophosphatemic ricks (PHEX gene)

Question 14

Difference between incomplete penetrance and expressivity?

Answer 14

incomplete penetrance = absent phenotype (even though mutation may be present)

Variable expressivity = disorder manifesting in different ways for those affected eg tuberous sclerosis

Question 15

rules for mitochondrial disease inheritence?

Answer 15

Both sexes affected
Transmission only by females

Question 16

What is ‘heteroplasmy’?

Answer 16

The presence of both normal and mutation-carrying mitochondrial DNA in a cell

Question 17

What is a non-sense mutation

Answer 17

Replacement of codon with a stop codon

Question 18

What is a mis-sense mutation

Answer 18

Mutation that results in an amino acid substitution (eg REPLACEMENT of a single nucleotide)

Question 19

What is a frameshift mutation?

Answer 19

Abnormal amino acid sequence due to insertion or deletion which causes a shift in the reading frame

Question 20

Which chromosomes are acrocentric (centromere off centre) and at risk of translocation?

Answer 20

Chromosomes 13, 14, 15, 21, 22

Question 21

What does microarray not detect?

Answer 21

Inversions
Balanced chromosome configurations and insertions

Question 22

How often does translocation occur to result in Down syndrome?

Answer 22

5% of cases are due to translocation, commonly between chromosomes 21 and 14
- problems arise at gametogenesis (not affected by maternal age) - risk of recurrence

Question 23

Most common genetic mutations in CF?

Answer 23

delF508 (~80%)
G551D (2.6%)
G542X (1.5%)
G85E (1.5%)

Question 24

Syndrome caused by Imprinting defect at 11p15/
Paternal uniparental disomy at 11p15

Answer 24

Beckwith Wiedemann

Question 25

Syndrome caused by imprinting defect at 11p15, maternal uniparental disomy at 11p15 or 7q?

Answer 25

Russell Silver Syndrome

Question 26

Features of Russel-Silver syndrome?

Answer 26

IUGR, short status, macrocephaly with triangular facies Cafe au lait spots clinodactytyl

Question 27

Features of stickler syndrome?

Answer 27

Cleft palate/ PRS Myopia, cataracts, retinal holes and detachments SNHL Joint hypermobilitya and MSK issues Mitral valve prolapse

Question 28

3 common features of congenital rubella syndrome?

Answer 28

Cataracts PDA Microcephaly

Question 29

Examples of histone acetylation defects?

Answer 29

Cornelia de lange syndrome, Kabuki Syndrome, Rubinstein-Taybi syndrome

Question 30

Examples of ribosomal trafficking defects?

Answer 30

Diamond blackfan anaemia, Schwachmann Diamond Syndrome, cartilage hair hypoplasia

Question 31

Example of telomere maintenance defect?

Answer 31

Dyskeratosis congenita

Question 32

Differences between Marfan syndrome and Loeys-Dietz syndrome?

Answer 32

In Loeys-Dietz: 1. Bifid or broad uvula 2. Hypertelorism 3. Twisted arteries 4. Aneurysms more common

Question 33

Features of 16p13.11 microduplication?

Answer 33

- Autism - Behavioural issues - risk factor for neuropsychiatric diagnoses - includes MYH11 gene which is associated with increased risk of aortopathy (aneurysms, dilatation)

Question 34

Most common gene mutation in Alagille syndrome?

Answer 34

JAG 1 (89%) NOTCH2 second most common

Question 35

Macroglossia, exomphalos, lateralised overgrowth, hyperinsulinism, risk of Wilms, ears creases and/or pits, umbilical hernia

Answer 35

Beckwith Wiedeman syndrome

Question 36

Features of Kabuki syndrome

Answer 36

CHD (70%) - usually L sided obstructive defects Cleft lip/palate (30%) ID/GDD Genitourinary issues (25%) Dysmorphism: arched eyebrows with eversion of lateral 1/2, depressed nasal tip, large cupped ears, long palpebral fissures Joint hyper mobility

Question 37

There is risk of sudden cardiac death with anaesthesia in which condition?

Answer 37

Williams Syndrome

Question 38

Fibrillin-1 mutation (FBN1) is seen in which condition?

Answer 38

Marfan syndrome

Question 39

Most common genetic cause for trisomy 21?

Answer 39

95% are due to non-disjunction during meiosis (failure of separation of chromosome homologues) 3-4% are due to translocation (commonly 14;21) 1-2% mosaicism

Question 40

Recurrence risk for trisomy 21 caused by translocation?

Answer 40

12% if mother is carrier 1% if father is carrier 100% if 21;21 translocation

Question 41

What is the risk of leukaemia in T21?

Answer 41

1 in 300 risk of ALL or AML for children with T21 (10-20 times increased RR)