Genetic Disordes Flashcards
3 triosmies
Downs - 21 - 1:700
Edwards - 18 - 1:8000
Pataus - 13 - 1:15000
Facial features of downs
Round, epicanthic folds, flat nasal bridge, small ears, protruding tongue, brushfield spots on iris (pigmented)
Non facial dysmorphic features downs
Wide sandal gap, incurring little fingers, single palmar crease
Structural defects downs
Cardiac in 50%
Duodenal atresia
Neurological feature downs
Hypotonia, developmental delay , decreased IQ (~50)
Late medical complications of downs
Increased risk of leukaemia (CML); Alzheimer’s; hypothyroidism; atlantoaxial instability
What is atlantoaxial instability
Excessive movement of atlas and axis on neck -> can cause nerve root compression
The 3 cytogenetic causes of downs (with%)?
Non dysjunction (94%)
Translocation (4%)
Mosaicism 1%
What happens in non-dysjunction
The two chromosomes 21 fail to separate so one gamete has 2 copies -> fertilisation of this gamete give a trisomy
Are non dysjunctions usually maternal or paternal? What increases risk? What’s the recurrence risk?
90% maternal.
Increasing age (over 35)
1 in 200 (if
What happens in translocation
The extra chromosome 21 is joined onto another chromosome (usually 14) giving rise to an unbalanced robertsonian translocation
The affected child has 46 chromosomes but still 3 copies of 21 material.
Recurrence risk in translocation
10-15% if mother
2-3% if from father
If the parent carried 21:21 translocation 100%
What happens in mosaicism ? How severe ?
Non dysjunction occurs during mitosis after fertilisation
Some cells have tri-21 and some don’t
Often has a milder phenotype
Genotype in tuner syndrome ? How common? How often does this result in miscarriage ?
45X
1:2500 live born female
95% miss carry
What’s seen on antenatal USS of turners
Oedema of the neck, hands, feet or a cystic hygroma
What are the cytogenetics of turners (physiology)?
50% have 1 X chromosome
50% have deletion in the short arm of 1 X chromosome (isochromosome - 2 long arms) or other structural defects
Dysmorphic features of turners
Lymphoedema of hands and feet at birth Neck webbing Short stature Shield chest (wide spaced nipples) Wide carrying angle
Structural / functional defects in turners
Gonadal dysgenesis (primary amenorrhoea) - streak ovaries
CHD - esp coarctation of aorta
Renal anomalies
Management of turners ? Explain rational of each?
Growth hormone to improve final height
Oestrogen therapy at 11 years -> allows development of secondary sexual characteristics
Klinefelter’s syndrome genetics? How common? Features? What mat be required?
47xxy
1:1000 live born males
Infertility, hypogonadism, gynaecomastia in adolescence ,tall stature
pubertal development usually normal but may need supplemental testosterone
Egs of some deletion syndromes ? Where are the deletions
Cri du chat syndrome - tip of chromosome 5
Dr’ George’s syndrome - in chromosome 22
William’s syndrome - long arm of chromosome 7
Features of cri du chat
High pitched cry in infancy “cri du chat’
How is analysis of dr George syndrome done? Features?
Cytogenetics analysis using FISH
Developmental delay, learning difficulty, ritualistic behaviour & obsessions, conductive hearing loss, T cell deficiency , hypocalcaemia
Why do dr George syndrome get conductive hearing loss? T cell deficiency?
Recurrent otitis media
Absent thymus
Features of Williams syndrome
Short stature, mild learning difficulty, CHD, transient neonatal Hypercalcaemia (sometimes), faces
What facial features in Williamsons ? What CHD?
Low nasal bridge, ‘elf-line’
Supra valvular aortic stenosis
AD single parent affected chance of passing on ?
50%
Eg of AD inheritance with variable expression
Tuberous sclerosis
What is non penetrance ? Eg?
Lack of signs and symtoms in individual who has the abnormal gene
Otosclerosis
What can cause no FHx of AD disorder
New mutation in gametes
Mosaicism
Non-paternity
Egs of AD diseases
Neurofibromatosis
Huntington’s
Achrondroplasia
Familial hypercholesterolaemia
Risk of AR disease if both parents are carriers? What can increase risk?
25%
Consanguinity
Egs of AR diseases
Cystic fibrosis, thalassaemia, sickle cell, congenital adrenal hyperplasia, inborn errors of metabolism
What happens in X linked disorders ? Who is affected?
Carrier female on 1 X chromosome (other is normal)
only males affected but females can be mildly
X linked disorder father ? Effect on children
All daughters are carriers
No sons are carriers
Egs of X linked disorders
Haemophilia , duchenne muscular dystrophy, fragile X syndrome, red/green colourblindness
How common is fragile X? What is it due to?
1:1000 males, 1:2000 females
Trinucleotide repeat of expansion of triplet repeat CGG in the FRAXA gene FMR1
Features of fragile X
Moderate-severe learning disability Macrocephaly Macro-orchidism (post pubertal) (Mitral valve prolapse, joint laxity, scoliosis, autism, hyperactivity) Faces
Facial features of fragile X
*Broad forehead
Large everted ears
Prominent mandible *
What are the two most common genetic causes of learning difficulties
Downs
Fragile X
How are mitochondrial disorders inherited ? Egs?
Maternally
*MELAS (to remember) *
Mitochondrial encephalopathy, lactic acidosis, stroke like episodes
What is genomic imprinting
Only one copy of the gene (from mother or father is expressed)
Maternal allele imprinted - only express paternal allele
Paternal allele imprinted - only express maternal
2 ways for a child to fail to inherit active gene?
- De novo deletion* - parental chromosomes normal with a new mutation
- uniparental disomy* - when a child inherits 2 copies of a chromosome from 1 parent and none from the other
Eg of imprinting? Where is defect ?
Paternal deletion - Prader-Willi syndrome
Maternal deletion - Angleman’s syndrome
Can get due to disomy too!!! Not just deletion
Both have defective gene at *15qII-B *
Features of prayer-Willi
Learning difficulty, obesity, hypotonia
Features of Angleman’s
“Happy puppet” - severe learning difficulty, ataxia, epilepsy, characteristic face
Basic elements of genetic counciling
Establishing a diagnosis
Estimation of risk
Communication
How do you establish a diagnosis?
Physical exam
Special investigations - DNA, cytogenetics, biochemical analysis
What risk do you have to calculate after a diagnosis
Chance of future offspring being affected
How do you communicate genetic disorders
Conveyed in an unbiased and non-directive way with all the possible options being discussed
