Genetics Flashcards
What is the inheritance pattern of familial hypercholesterolaemia?
autosomal dominant
What criteria is used to diagnose familial hypercholesterolaemia?
Simon-Broome criteria - definite or possible FH
What are the Simon-Broome criteria for definite familial hypercholesterolaemia?
Total cholesterol >7.5 + LDL >4.9 + tendon xanthomata in patient OR in first or second degree relative
OR
identified genetic mutation for FH
What are the Simon-Broome criteria for possible familial hypercholesterolaemia?
Total cholesterol >7.5 + LDL >4.9 + 1 or more of the following:
* FH early MI <60y in 1st degree relative or <50y in 2nd degree relatie
* FH raised TC - >7.5 in first or second degree adult relative or >6.7 in brother, sister or child <16y
What is the commonest cardiac defect in Down syndrome and what are 4 others?
AVSD (VSD, ASD, PDA, Tetralogy of Fallot)
What is the equation to calculate the risk of giving birth to a baby with Downs based on mother’s age?
risk = 1/1000 at 30 years, then divide by 3 for every 5 years beyond 30 (e.g. 45 years old - 1 in 50 or greater)
What are the 3 genetic mechanisms that can lead to Down syndrome and their relative frequencies?
- Non-disjunction - 94%
- Robertsonian translocation (onto chromosome 14 usually) - 5%
- Mosaicism - 1%
If a mother is <35y, what is the chance of a second child with Downs?
1 in 100 (higher if due to translocation)
What are 5 features of Patau syndrome?
- Microcephalic
- small eyes
- cleft lip / palate
- polydactyly
- scalp lesions
What is the genetic abnormality in Patau syndrome?
Trisomy 13
What is the genetic abnormality in Edward’s syndrome?
trisomy 18
What are 4 features of Edward’s syndrome?
- micrognathia
- low-set ears
- Rocker-bottom feet
- overlapping of fingers
What are 5 features of fragile X syndrome?
- learning difficulties
- macrocephaly
- long face
- large ears
- macro-orchidism
What are 4 features of Noonan syndrome?
- Webbed neck
- Pectus excavatum
- Short stature
- Pulmonary stenosis
What are 3 features of Pierre-Robin syndrome?
- Micrognathia
- Posteiror displacement of tongue (may cause upper airway obstruction)
- Cleft palate
What are 3 features of Prader-Willi syndrome?
- Hypotonia
- Hpogonadism
- Obesity
What are 5 features of William’s syndrome?
- Short stature
- Learning difficulties
- Friendly, extrovert personality
- Transient neonatal hypercalcaemia
- Supravalvular aortic stenosis
What are 6 features of Cri du Chat syndrome?
- Characteristic cry due to larynx / neuro problems
- Feeding difficulties, poor weight gain
- Learning difficulties
- Microcephaly
- Micrognathism
- Hypertelorism (increased distance between 2 body parts)
Which condition does Pierre-Robin syndrome resemble?
Treacher-Collins syndrome - this is autosomal dominant so FH prevalent
What is the genetic abnormality in Cri du Chat syndrome?
chromosome 5p deletion syndrome
What is the inheritance pattern of dystrophinopathies (Duchenne muscular dystrophy and Becker muscular dystrophy)?
X-linked recessive
What causes dystrophinopathies?
- mutation in gene encoding dystrophin, dystrophin gene on Xp21
- dystrophin is part of large membrane associated protein in muscle which connects muscle membrane to actin (part of muscle cytoskeleton)
What causes Duchenne muscular dystrophy?
frameshift mutation resulting in one or both binding sites being lost, leading to severe form
What is the inheritance pattern of familial hypercholesterolaemia?
autosomal dominant
What causes Becker muscular dystrophy?
non-frameshift insertion in dustrophin gene - results in both binding sites being preserved
What is the presentation of Duchenne muscular dystrophy? 4 features
- progressive proximal muscle weakness from age 5
- calf pseudohypertrophy
- Gower’s sign (using arms to stand from squatting)
- intellectual impairment 30%
What age does Becker muscular dystrophy tend to develop?
after age 10
How common is intellectual impairment in Duchenne vs. Becker muscular dystrophy?
much less common in Becker
What type of cholesterol is high in familial hypercholesterolaemia?
LDL
What 2 criteria do NICE suggest should suggest familial hypercholesterolaemia in adults?
- total cholesterol > 7.5
- personal or FH premature coronary heart disease (< 60 years)
How should children of parents with familial hypercholesterolaemia be managed?
- one parent with familial hypercholesterolaemia - arrange testing by age 10
- if both parents - arrange testing in age 5
What is the name of the criteria which allows a clinical diagnosis of familial hypercholesterolaemia?
Simon Broome Criteria
What are the 3 groups of Simon Broome criteria for familial hypercholesterolaemia?
- Adults: total cholesterol > 7.5 and LDL > 4.9; children TC > 6.7, LDL > 4.0 PLUS
- definite diagnosis: tendon xanthmoa in patients or 1st or 2nd degree relatives, or DNA-based evidence
- possible diagnosis: FH of MI < 50 y in 2nd degree relative, < 60 y in first degree relative, FH raised cholesterol
What is the management of familial hypercholesterolaemia?
- refer to specialist lipid clinic
- high dose statins
- screen first degree relatives
When should statins be discontinued in women with familial hypercholesterolaemia and why?
3 months before conception - risk of congenital defects
What are 7 key features of Turner’s syndrome?
- short stature
- shield chest, widely spaced nipples
- webbed neck
- cardiac: bicuspid aortic valve + coarctation of aorta
- primary amenorrhoea
- high-arched palate
- short ring fingers (short fourth metacarpal)
What are 4 classic cardiac abnormalities in Turner’s syndrome?
- bicuspid aortic valve
- coarctation of the aorta
- increased risk of aortic dilatation
- increased risk of aortic disscetion
What is the most common renal abnormality in Turner’s syndrome?
horseshoe kidney
What is a key blood test finding in Turner’s syndrome?
elevated gonadotrophin levels
Which type of genetic abnormalities are particularly prone to demosntrating anticipation?
trinucleotide repeat disorders
What are 7 examples of trinucleotide repeat disorders (prone to anticipation)?
- Fragile X
- Huntington’s
- myotonic dystrophy
- Friedrich’s ataxia
- spinocerebellar ataxia
- spinobulbar muscular atrophy
- dentatorubral pallidoluysian atrophy
What is the commonest cardiac problem in Down’s syndrome?
endocardial cushion defect (aka atroventricular septal canal defects)
What are 2 GI problems which may be seen in Down syndrome?
- duodenal atresia
- Hirschprung disease
How does subfertility in Down syndrome occur in males vs females?
- males: almost always infertile (impaired spermatogenesis)
- females: usually subfertile, increased incidence of problems with pregnancy and labour
What is the commonest type of cancer seen in Down syndrome?
acute lymphoblastic leukaemia
What MSK is seen as a later complication in Down syndrome?
atlantoaxial instability
Which chromosome is the genetic abnormality in Huntington’s disease on?
chromosome 4 (huntingtin gene)
What is the commonest inherited autosomal recessaive ataxia in the UK?
Friedrich’s ataxia
What are patients with Friedrich’s ataxia most likely to die from?
cardiomyopathy
What are 5 presenting symptoms of Friedrich’s ataxia?
- unsteadiness of gait
- general clumsiness or deterioration in athletic performance
- scoliosis
- pes cavus
- progressive ataxia, dysarthria, decreased proprioception/vibration sense and muscle weakness
