Genetics

Question 1

Explain X-linked conditions

Answer 1

Generally X linked dominant e.g. Alport syndrome, and X-linked recessive e.g. colour blindness (but some dispute over dropping terms because of different genetic mechanisms). Both M+F affected, but males usually more severely

In X-linked recessive men are usually affected (as only one X chromosome) and women usually carriers (as to have both less likely), e.g. Haemophilia

Question 2

Why does Turner’s syndrome only affect women?

Answer 2

there is only one chromosome and it is an X

therefore they cannot be male

Question 3

Autosomal recessive?

Answer 3

Need 2 affected genes to be passed on (one from each parent), carriers have 25% chance of child being affected

Usually ‘metabolic’ e.g. glycogen storage diseases, PKU, sickle cell, thalassaemia

Question 4

Autosomal dominant?

Answer 4

Only need 1 affected gene, homozygotes + heterozygotes manifest disease (so no carriers, so only affected people can pass it on)

Usually appears in every generation, unless is common to get spontaneous mutations

Usually structural e.g. APKD, FAP/HNPCC, hereditary haemorrhage telangiectasia, hereditary spherocytosis

Question 5

Cause of Down syndrome?

Answer 5

Non-disjunction most common - related to maternal age usually but can be from the sperm - chromosome 21 pair doesn’t separate @ meiosis so get an zygote with 3 chromosomes

Can also be through translocation, or mosaicism (rare, some cells T21 and some cells normal)

Question 6

Features of Down syndrome?

Answer 6

• Craniofacial appearance: round face, flat nasal bridge, up slanted palpebral fissures, epicanthic folds, Brushfield spots in iris, small mouth + protruding tongue, small ears, flat occiput, 3rd fontanelle
• Other anomalies: short neck, single palmar crease, short 5th metacarpal, wide gap between 1st+2nd toe, hypotonia, duodenal atresia, Hirschsprung disease (uncommon)
• Heart disease (major cause of death): AVSD (most common), VSD
• Later complications: delayed motor milestones, LD< short stature, more infections, hearing impairment (secretory otitis media), vision (cataract, squint, myopia), higher risk of leukaemia + solid tumours, acquired hip dislocation, atlanto-axial instability, OSA, hypothyroidism, coeliac disease, epilepsy, early onset Alzheimer’s

Over half live over 50y

Question 7

Features of Turner syndrome?

Answer 7

Low risk of recurrence

• Neonates-lymphoedema
• Skin - koilonychia, pigmented naevi
• Morphology - short, webbed neck, wide carrying angle (cubitus valgus), widely spaced nipples
• Organs: CHD (esp coarctation of the aorta + bicuspid aortic valve), ovarian dysgenesis, hypothyroidism, renal anomalies, recurrent otitis media
• usually normal IQ
• Delayed puberty, infertility (IVF possible with donated eggs)

M: GH, oestrogen to develop secondary characteristics at puberty age (but infertility persists)

Question 8

Klinefelter syndrome?

Answer 8

47, XXY
This is males with an extra X chromosome
Infertility commonest presentation, hypogonadism (but some have normal puberty), gynaecomastia, tall, usually normal intelligence but may have educational issues

Question 9

Duchenne muscular dystrophy

Answer 9

X-linked recessive but 1/3 new mutations - deletion of dystrophin protein (which connects muscle fibre cytoskeleton to ECM)

CF: waddling gait, language delay, mount stairs one by one, run slowly (average diagnosis at 5y but symptoms may be earlier)

• Gower’s sign (turn prone to rise)
• Pseudohypertrophy of calves (muscle replaced with fat)

Ix: creatine kinase very raised (often x10-100 of normal) [if CK not raised DMD is unlikely], abnormal LFT in a baby (may then check CK)

Comps: scoliosis, atrophy + weakness, stop walking early adolescence, life expectancy late 20s cos of resp failure/cardiomyopathy

M: PT to prevent contractures, may need scoliosis/Achilles surgery, overnight CPAP, steroids to preserve mobility

Identify female carriers through mildly high CK, or gene deletion on DNA analysis

Question 10

Achondroplasia

Answer 10

AD, but half new mutation - in fibroblast growth factor receptor gene

CF: short stature, large head, frontal bossing, depressed nasal bridge, short + broad hands, lumbar lordosis. Torso often normal length. IQ normal

M: GH, support groups

Question 11

Foetal alcohol syndrome features

Answer 11

Growth restriction, saddle shaped nose, maxillary hypoplasia, absent philtrum, short thin upper lip, developmental delay, cardiac defects, microcephaly

Question 12

Marfan syndrome

Answer 12

AD defect in fibrillin

CF: tall, arachnodactyly (long thin digits), hyperextensible joints, high arched palate, lens dislocation, severe myopia, chest deformity, scoliosis, arm span > height, CV problems (incompetent aortic root, valve incompetence esp MV prolapse/regurgitation, aortic aneurysms [may dissect or rupture])

Question 13

Phenylketonuria

Answer 13

IEM - can cause LD, seizures, microcephaly

Pick up on blood spot so can avoid this – restrict phenylalanine in diet. So no beans, nuts, meat, fish, dairy, eggs, cheese, wholegrains (what do they even eat the poor things)

Question 14

Patau syndrome

Answer 14

T13

Microcephaly, small eyes, cleft lip/palate, polydactyly, scalp lesions

Question 15

Edward syndrome

Answer 15

T18

Micrognathia, low set ears, rocker bottom feet, overlapping of fingers

Question 16

Fragile X

Answer 16

LD, macrocephaly, long face, high arched palate, large ears, macro-orchidism, MV prolapse, autism

Question 17

Noonan syndrome

Answer 17

Webbed neck, pectus excavatum, short stature, pulmonary stenosis

Question 18

Pierre-Robin syndrome

Answer 18

Micrognathia, posterior displacement of tongue, cleft palate

Question 19

Prader-Willi vs Angelman syndrome

Answer 19

Imprinting: phenotype depends on if deletion occurs on gene from mother or father:
Prader-Willi syndrome if gene deleted from father,
Angelman syndrome if gene deleted from mother

PWS (most commonly 15q11-13 deletion): hypotonia, dysmorphic, short, obesity, hypogonadism, LD, behavioural

Angelman syndrome: mostly affects nervous system. usually happy personality but small head, dysmorphic face, developmental delay, severe LD, ataxia, speech impairment, seizures

Question 20

William’s syndrome

Answer 20

Short, LD, friendly extroverted personality, transient neonatal hypercalcaemia, supravalvular aortic stenosis, elfin facies, strabismus, broad forehead

Question 21

Cri du chat syndrome

Answer 21

Chromosome 5p deletion

Characteristic cry (larynx + neuropathy problem), feeding difficulties, poor weight gian, LD, microcephaly, microganthism, hypertelorism (usually bigger distance between eyes)

Question 22

What is the transmission of X-linked conditions?

Answer 22

There is no male-to-male transmission!

In X-linked dominant they can have affected daughters but not affected sons, unless the mother is also affected (if she has the dominant allele)

In X-linked recessive affected men can have unaffected son + carrier daughter; a male child of a female carrier has a 50% chance of being affected and female child 50% chance of being a carrier

Question 23

Inheritance of ABO blood grouping

Answer 23

Co-dominant: both alleles influence the trait

Question 24

Turner’s syndrome is X-linked recessive so why are females the only people affected?

Answer 24

Turner syndrome - females only have one X-chromosome (or one full and one partial)

so it’s 45, X (as they only have 45 chromosomes; whereas a normal female would be 46, XX and a normal male 46, XY)

there is no Y chromosome so not male

Question 25

What are the most common complications of Down syndrome?

Answer 25

• CHD: AVSD, VSD
• Hypothyroidism
• Hearing impairment due to secretory otitis media

Question 26

Explain mitochondrial inheritance

Answer 26

• Some dsDNA is in the mitochondria
• Inheritance only via maternal line, as sperm contributes no cytoplasm to the zygote
• Any child of an affected male will NOT inherit
• Any child of an affected female WILL inherit
• Usually these are rare neurological diseases

Question 27

What does histology typically show for mitochondrial conditions?

Answer 27

Muscle biopsy - red ragged fibres, due to increased number of mitochondria

Question 28

Give some examples of mitochondrial diseases

Answer 28

• Leber’s optic atrophy
• MELAS syndrome: mitochondrial encephalomyopathy, lactic acidosis + stroke-like episodes
• Some types of sensorineural hearing loss