Genetics Flashcards
What can happens to chromosomes to bring about a chromosome disorder?
DELETION DUPLICATION TRANSLOCATION TRISOMY MOSAICISM (abnormal: structure, extra portion or extra number)
Example of a deletion chromosome disorder?
Portion of chromosome is missing.
Very rare.
“CRI DU CHAT” missing part of chromosome 5:
- learning, developmental and speech and language difficulties
- “cat like cry” as infants
Example of a duplication chromosome disorder?
CHARCOT-MARIE-TOOTH duplication of short arm of Chromosome 17:
- sensory and motor neuropathy
- characteristic “pes cavus” (high arching foot)
Portion of chromosome is duplicated, has twice the copies for some of the genes.
What is and examples of translocation chromosome disorder?
Portion of chromosome is switched into another (reciprocal or nonreciprocal).
No specific syndrome but increase risks other conditions (cancer, infertility etc):
PHILADELPHIA chromosome
- Acute Myeloid Leukaemia. Reciprocal translocation, Chr 9 and Chr 22.
ROBERTSONIAN translocation in acrocentric (long arm) chromosomes 13, 14, 15, 21, 22. Short arm is lost so just two long arms, makes it look like one chromo is lost. Phenotypically normal but only 45 chromosomes when counted - risk for offspring.
Examples of trisomy chromosome disorders?
PATAU syndrome - trisomy 13
EDWARDS syndrome - trisomy 18
DOWNS syndrome - trisomy 21
What are the features of Patau and Edwards syndrome?
PATAU syndrome - trisomy 13:
- microcephalic, holoprosencephaly
- small eyes - cleft lip / palate
- “rocker bottom feet” = convex soles
- polydactyly
- scalp lesions
- cardiac defects, cystic kidneys
What are the features of Edward’s syndrome?
EDWARDS syndrome - trisomy 18:
- micrognathia (small jaw), prom occiput
- low-set ears
- “rocker bottom feet” = convex soles
- overlapping fingers, clenched hands
- VSD, omphalocele, meckels diverticulum, horseshoe kidney, malrotation
What happens in mosaicism chromosome abnormality?
Happens after conception. Abnormality is in a portion of cells but not other. Each case is unique and unpredictable.
What diseases show mitochondrial inheritance?
Mitochondrial disease are myopathies and muscles have “red, ragged fibres”.
Heteroplasmy - poor genotype:phenotype correlation.
LEBER’S optic atrophy:
- painless vision loss in adolescents
MELAS syndrome:
- Mitochondrial Encephalomyopathy Lactic Acidosis and stroke-Like episodes
MERRF syndrome (encephalopathy not myopathy):
- Myoclonus Epilepsy with Ragged-Red Fibres
KEARNS-SAYRE syndrome:
- ophthalmoplegia
- retinitis pigmentosa
- onset <20yo
- possible ptosis
- heart block SENSORINEURAL hearing loss
What are the different ways of genetic testing?
KARYOTYPING
- looking at number, size and shape of the chromosomes (Patau, Edwards, Downs)
MICROARRAY
- enzymes cut up genes which then spread on plate according to weight, eg CF gene is heavier so you get a clump there
SPECIFIC GENE TESTING
- split the DNA strands and then add a gene probe to look for a specific gene. DNA sequencing - only used in research, split strands and add nuceotides
Downs syndrome dysmorphic features and complications?
FEATURES:
- hypotonia
- brachycephaly (small head with flat back)
- short neck, short stature
- flat face and nose
- prominent EPICANTHIC folds
- upward sloping PALPEBRAL fissures
- single PALMAR crease (simian crease)
COMPLICATIONS:
- learning disability
- dementia in adults
- recurrent otitis media
- deafness; Eustachian tube abnormal leads to glue ear and conductive hearing loss
- visual; myopia, strabismus, cataracts
- atlantoaxial instability
- hypothyroidism
- cardiac; ASD, VSD, PDA, tetralogy
- duodenal atresia, Hirschsprungs
- leukaemia (ALL)
There is screening and testing for Down’s, what are the screening tests?
COMBINED TEST 11-14 weeks US and blood, inc risk:
- Nuchal translucency over 6mm
- inc BETA-HCG
- dec PAPPA (pregnancy associated plasma protein A)
TRIPLE TEST 14-20weeks, blood only, inc risk:
- inc BETA-HCG
- dec AFP dec SERUM OESTRIOL
QUADRUPLE TEST 14 -20 weeks, same as triple but with:
- risk inc with INHIBIN-A Test give risk score, greater than 1 in 150 then offered testing (5% of pregnancies)
After screening what are the antenatal tests you can do for Down’s?
INVASIVE (foetal cells and karyotype them)
- before 15 weeks: CHORIONIC VILLOUS SAMPLING (placental tissue)
- beyond 15 weeks: AMNIOCENTESIS (amniotic fluid)
NON-INVASIVE prenatal testing
- NIPT, DNA fragments in maternal blood
Management of Down’s?
OSCE q.
MDT:
- OT
- SALT
- physio
- dietician
- paediatrician
- GP
- health visitors
- cardiologist
- ENT for ear
- audiologist
- optician
- social services for care and benefits
- educational support
- charities such as Downs Syndrome Association
INVESTIGATIONS:
- regular thyroid (2yrs)
- echo for heart defects
- regular audiometry
- regular eye check
Average life-expectancy is 60 years
What are happens in Klinefelter syndrome? What are the features? Management and prognosis?
Male with additional X Chr, so 47 XXY or 48 XXXY.
Dx by karyotype (may see Barr body of extra chromo).
- taller height, wide hips, long extremities
- gynaecomastia
- weak muscles
- small testicles, reduced libido, infertile
- shy, learning difficulties
- low testosterone, low inhibin B, high LH and FSH, high oestrogen
MANAGEMENT:
- testosterone injections
- IVF for fertility
- breast reduction surgery
- MDT; SALT, OT, physio, education support
Almost normal life expectancy, some increased risk of breast cancer, osteoporosis, diabetes, anxiety and depression.
What happens in Turners syndrome? Features? Associated conditions and management?
Female has just single X chr, so 45 X0.
- short
- webbed neck (cystic hygroma)
- high arching palate
- downward sloping eyes with ptosis
- broad chest, wide nipples (shield chest)
- cubitus valgus
- underdeveloped ovaries (streak)
- infertile
- incomplete puberty
- lymphoedema hands and feet
- dec oestrogen, inc FSH and LH
ASSOCIATED:
- recurrent otitis media and UTI
- Ao coarc, bicuspid Ao valve
- hypothyroid common
- HTN
- obesity, diabetes
- osteoporosis
- learning difficulty
- ovary dysgerminoma
MANAGEMENT:
- growth hormone therapy for short stature
- oestrogen and progesterone for secondary sex characteristic and osteoporosis
- fertility treatment
- life expectancy almost normal.
What is Noonan syndrome? Features and associated conditions? Management?
Majority are autosomal dominant on chromosome 12. Normal karyotype. (Features are like Turner’s but for both sexes)
- short stature
- broad forehead
- webbed neck
- wide nipples, chest carinatum / excavatum
- down sloped eyes with wide space (hypertelorism)
- low set ears
- triangle shape face
ASSOCIATED:
- pulmonary valve stenosis, ASD, hypertrophic cardiac myopathy
- cryptorchidism and infertility in men
- learning difficulty
- bleeding disorder; factor XI deficiency
- lymphoedema
- increased risk leukaemia and neuroblastoma
MANAGEMENT:
- supportive and MDT
- heart disease; corrective surgery
What happens in Marfan’s syndrome and what are the features? Management?
Autosomal dominant on chr 15 defect in FBN1 gene for FIBRILLIN in connective tissue.
- tall, long neck, long limbs
- dislocation and hypermobility
- scoliosis of spine >20 degrees
- arachnodactyly (long fingers)
- pes planus
- high arch palate
- downward palpebral fissures
- lens dislocation in eye
- pectus carinatum / excavatum
- pneumothorax
- gastro oesophageal reflux
- MITRAL VALVE PROLAPSE
- AO VALVE PROLAPSE
- ao anyurysms
OSCE tests for arachnodactyly:
- thumb fold across palm and beyond (Steinberg sign) and fingers wrap around wrist (Walker-Murdoch sign)
- murmurs of mitral or Ao regurg
- palate, arm span, hypermobility (Beighton 5 score)
MANAGEMENT:
- cardiac risk; surgically correct prolapse etc
- minimise blood pressure and heart stress
- beta blockers nad ARBs
- pregnancy risk of Ao aneurysms
- physio
- genetic counselling for having kids
- echos and ophtho yearly
What happens in Fragile X? Features? Management?
CGG trinucleotide repeat disorder on X chr in the FMR1 gene (fragile x mental retardation 1).
X-linked but unclear if dominant or recessive, males alway but females variable.
FEATURES:
- intellectual disability /mental retardation
- long narrow face, large jaw
- large ears
- large testicles after puberty
- hypermobile esp hands
- ADHD
- ASD
- seizures
MANAGEMENT:
- normal life expectancy
- manage ADHD, ASD, learning, seizures
What happens in Prada-Willi syndrome? Features and management?
Loss of genes from proximal arm of chr 15 from the father (either from deletion or both copies from mother as maternal is imprinted ie off).
FEATURES:
- hypotonia (floppy baby)
- insatiable hunger, obesity (more ghrelin)
- learning disability
- hypogonadism
- fair skin, brusing
- anxiety
- dysmorphic features
- narrow forehead
- almond shaped eyes
- strabismus
- thin upper lip
- downturned mouth
MANAGEMENT:
- limit food acces to control weight
- locks on fridge, cupboard, bins
- GROWTH hormone to improve muscles - MDT
What happens in Angleman syndrome? Features? Management?
Loss of mothers UBE3A gene on long arm of chr 15q, either from two paternal copies or mutation in mothers. (paternal imprinted)
FEATURES:
- fascination with water
- happy demeanour
- innappropriate laughter
- hand flapping
- wide based ataxia
- abnormal sleep
- epilepsy (slow spike EEG)
- ADHD
- microcephaly, dysmorphic features
- fair skin, light blue eyes
- wide mouth, WIDELY spaced teeth aka “happy puppet syndrome”
MANAGEMENT:
- MDT: social services and support, parental education, physio, OT, psych, CAHMS, anti-epileptics
What happens in Williams syndrome? Features and management?
Random deletion around conception on one copy of chr 7q (for elastin).
FEATURES:
- “elfin” like faces
- broad forehead
- STARBURST eyes
- flattened nasal bridge
- long philtrum (nose to lip)
- wide mouth, wide spaced teeth
- small chin - sociable and trusting
- mild learning disability
- SUPRAVALVULAR AO STENOSIS
- HYPERCALCAEMIA
- ADHD
- HTN
MANAGEMENT:
- MDT
- echo and BP for Ao stenosis and HTN
- low calcium diet (avoid vit D supplements) (FISH diagnosis)
