Genetics Flashcards
cause of down syndrome
meiotic non disjunction most common during oogenesis (94%)
maternal nondisjunction is cause in 88%
47XX/XY + 21
unbalanced robertsonian translocation (5%) -> family history
what are the screening bloods tests offered for downs syndrome
10-14 weeks: beta hcg + pregnancy associated plasma protein + ultrasound scan +maternal age
= gives estimated risk of downs syndrome (picks up 84%)
14-20 weeks: beta hcg, alpha fetoprotein, inhibin A and unconjugated oestradiol
calculates risk of downs with maternal age
if risk of downs more than 1 in 150 -> offered diagnostic test -> CVS (10-13 weeks gestation) or amniocentesis (16 -20 weeks). both have 1% risk of miscarriage
dysmorphic features of downs syndrome
- epicanthic folds
- flat nasal bridge
- single palmer crease
- large sandal gap
- low set small ears
- brushfiedl iris spots
- short stature
- protruding tongue
- short neck
Other features and conditions associated with downs syndrome
- ears: otitis media with effusion
- eyes: strabismus, nystagmus, cataracts
- heart: AVSD, VSD
-CNS: hypotonia, developmental delay, alzheimers risk - hypothyroid
- haem: ALL. AML
- Gastro: GORD, duodenal atresia, coeliac, pyloric stenosis, hirschsprungs diosease, meckels diverticulum, tracheo-oesophageal atresia
How to test for downs syndrome
QF-PCR for chromosome 21 ** + karyotype
what are the features of edwards syndrome (trisomy 18)
- low set ears
- prominent occiput
- small mouth and chin
- cleft palate
- overlapping fingers and clenched fists
- small birth weight and IUGR
- rocker bottom feet
- ASD, VSD, PDA
What are the features of patau syndrome (trisomy 13)
- cleft lip and palate
- small eyes
- polydactyly
- structural defect of brain
how do you diagnose turners sydnrome
Karyotype
what are the physical features of turners syndrome
- wide spaced nipples
- short stature
-webbed short neck - low hairline
- scoliosis
- non pitting lymphoedema
which conditions is Turners syndrome associated with?
- coarction of aorta, bicuspid valve
- hypothyroidism
- gonadal dysgenesis : premature ovarian failure and delayed puberty
- horseshoe kidney, renal aplasia, duplicated ureters
- recurrent otitis media
How can you manage Turners syndrome?
- growth hormone
- oestrogen replacement therapy
what is the cause of Klinefelters syndrome
47 XXY
non disjunction in stage 1 of meiosis causes additional Y chromosome and forms barrs body
How do Klinefelters syndrome present at puberty?
- poor growth
- small testes
- gynaecomastia
- truncal obesity
- tall stature
- mild development and behavioural problems
Which conditions is Klinefelters syndrome associated with?
breast cancer
hypothyroid
mitral valve prolapse
osteoporosis
autoimmune disease
leukaemias
management of Klinefelters
testosterone
Genetic mutation in William syndrome
microdeletion of chromosome 7 (7q11.23)
diagnosis of william syndrome
FISH or chromosomal miroarray
features of william syndrome
- broad forehead
- wide mouth and prominent upper lip
- supraclavicular aortic stenosis + pulmonary artery stenosis
- hypercalcaemia
- learning difficultues but strong social skills
- affinity for music
- outgoing personality
- ## blue iris and blond hair
genetic cause of DiGeorge syndrome?
22q11 microdeletion syndrome (reduction in T box transcription factor 1) and disrupts development in the 3rd and 4th pharyngeal arch
defect in neural crest cells
clinical features of DiGeorge syndrome
C - cardiac - ToF, interrupted aortic arch
A- abnormal facies e.g. narrow palpebral fissures, high broad nasal bridge, short philtrum
T- thymic aplasia - immunodeficiency
C- cleft palate
H- hypocalcaemia and hypoparathyroidism
22
- scoliosis, behavioural disorders, poor growth, renal agenesis
inheritance of noonan syndrome
autosomal dominant
genetic cause of noonan syndrome
mutation in PTPN11 gene on chromosome 12 ** or mutation in SOl1 gene on chromosome 2
clinical features of noonan syndrome
- short stature
- triangular shaped face, down slanting parapebral fissures, short webbed neck, low set ears
- strabismus, ptosis
- pectus excavatum, wide spaced nipples
- heart : pulmonary valve stenosis, hypertrophic cardiomyopathy
- VWF disease, thrombocytopenia
genetic cause of Tay sachs
frameshift mutation in HEXA gene on 15q23-q24 causing failure to break down GM2-GANGLIOSIDE - which then accumulates in neurones and causes neurodegeneration
decreased lysosomal hydrolysis
inheritance of Tay sachs disease
autosomal recessive
presentation of tay sachs disease at 3-6 months old
myoclonic jerks, exaggerated startle reflex
presentation of tay sachs disease at 6-10 months old
developmental regression, hypotonia, seizures
presentation of tay sachs disease over 5 y/o
confusion, ataxia, macular cherry red spot, death secondary to resp failure
how is tay sachs disease diagnosed
enzyme activity of hexa A
inheritance of phenylketonuria
autosomal recessive
genetic cause of phenylketonuria
phenylalanie hydroxylase deficiency causing phenylalanine (inhibits cerebral uptake of tyrosine and tryptophan) to accumulate in brain
can be metabolised to phenyl ketones
tetrohydrobiopterin cofactor for conversion of phenlylalanine to tyrosine and also implicated in the disease
clinical features of phenylketonuria
- vomiting
- musty odour
- seizures, spasticity, tremors
- hyperactivity, autism, purposeless hand movements
facial features of phenylketonuria
fair hair, eyes, hair
microcephaly
wide spaced teeth
prominent maxilla
enamel hypoplasia
phenylketonuria management
- phenylketonuria restricted diet - XP anologue LCP milk (phenylalanine free milk)
- large amino acids e.g. tryptophan, tyrosine
- tetrahydrobiotin
inheritance of fragile X syndrome
X linked dominant
genetic cause of fragile X syndrome
repeat expansion disorder of CGG repeats on FRM1 gene
clinical features of fragile X syndrome
- developmental delay, learning difficulties (most common cause in boys), ADHD
- recurrent otitis media
- high forehead
- large jaw
- long ears
- narrow elongated face
- hyper extendable finger joints
risks for women with fragile X
more common in women
50% risk of premature ovarian failure or early menopause
inheritance of Rett syndrome
X linked dominant or sporadic mutation in MECP2 gene
Clinical features of Rett syndrome
child born healthy and then developmental regression around 6-18 months…
- involuntary hand movements e.g clapping, hand wringing
- apraxia
- teeth grinding
- dysphagia, poor weight gain, feeding difficulty
- involuntary behaviour e.g. laughing
- hypertonia, spasms, seizures, vacant speels
- aspiration pneumonia
genetic inheritance of Prader willi syndrome
Imprinting: deletion occurs in paternal chromosome 15q11-13 so child lacks paternal copy of this region
presentation of prader willi syndrome
- severe neonatal hypotonia
- difficulties feeding in newborn stage
- obesity and short stature
- hypogonadism
- behavioural difficulties - tantrums, temper
- narrow forehead, almond eyes, thin upper lip, small hands and feet
complications of prader willi syndrome
- hypothyroid
- learning difficulties
- OSA
- osteoporosis
diagnosis of prader willi syndrome
DNA methylation specific testing or FISH
Management of prader willi syndrome
growth hormone therapy
inheritance of angelman syndrome
failure to inherit a functioning maternal copy of chromosome region 15q11-13
or paternal uniparentaldisomy of chromosome 15
features of angelman syndrome
ataxia and tremor
epilepsy
‘happy children’- smiling and laughter
severe developmental delay
microcephaly
inheritance of marfan syndrome
autosomal dominant
genetic cause of marfans
missense mutation on chromosome 15q21 which codes for fibrillin 1 which is needed for cellular microfibrins and regulation of TGF-BETA
physical features of marfans disease
- tall stature with long limbs
- scoliosis
- pectus excavatum
- down slanting palpebral fissures
- malar hypoplasia
- high narrow arched palate
- striae
- myopia and ectopia lentis
- risk of spontaneous pneumothorax
cardiac conditions associated with marfans
aortic root dilatation
mitral valve prolapse (pan systolic murmur)
aortic dissection (give beta blockers and ACE-I)
marfans diagnosis
2010 revised ghent nosology clinical criteria and molecular gene testing
inheritance of incontinenti pigmenti
X linked dominant
genetic cause of incontinenti pigmenti
mutation in IKBKG gene
clinical features of incontinenti pigmenti
- skin rash vesicular /blisters -> watery papular lesions -> hyperpigmented ‘marbled tablecloth’ -> atrophic and hair loss
- dental abnormalities
- seizures
- developmental delay
-females
(males miscarry)
inheritance of fanconi anaemia
autosomal recessive
features of fanconi anaemia
- bone marrow failure
- congenital abnormalities e.g. cafe au lait macules, hypoplasia of thumb
- increased cancer risk
- developmental; delay and short stature, hypogonadism, dysplastic limbs
diagnosis of fanconi anaemia
chromosome breakage test
management of fanconi anaemia
stem cell transplant
inheritance of galactosaemia
autosomal recessive
genetic cause of galactosaemia
mutation and deficiency in GALT enzyme so inability to metabolise lactose and galactose
causes accumulation of gal-1-p and UDP
features of galactosaemia
- early jaundice
- hepatomegaly
- oil drop cataracts
- e.coli infections
- developmental delay and seizures
- feeding difficulties and faltering growth
- diarrhoea
diagnosis of galactosaemia
quantitative assay of RBC GALT activity (reduced) and genetic testing
high GAL-1LP levels
high galactose levels in blood and urine
high galacitol
management of galactosaemia
dietary modification - lactose and galactose free diet
casein hydrolysate formula for babies
features of CHARGE syndrome
C- coloboma
H- herat defects
A- choanal atresia
R- retardation of growth and development
G- genital abnormalities
E - ear abnormalities - absent/ semi circular ear canals
genetic cause of beckwith wiedeman syndrome
abnormality of chromosome 11p15 (microdeletion)
clinical features of beckwith wiedeman syndrome
- macrosomia
- macroglossia
- ear pits
- increased risk of malignancies e.g. wilms tumour, hepatoblastoma
surveillance of beckwith wiedeman syndrome
abdo USS every 3 months until age of 8
serum alpha fetoprotein level every 2-3 months until age of 4
inheritance of duchenne muscular dystrophy
X linked recessive
(females asymptomatic)
genetic cause of duchenne muscular dystrophy
mutation in dystrophin gene so produce no dystrophin
(gonadal mosaicism worsens phenotype)
presentation of duchenne muscular dystrophy
progressive proximal muscle weaknee
gowers sign (difficulty to stand from sitting)
trendelenburgs gait
by adolesence, require wheelcahir
dilated cardiomyopathy
resp failure
diagnosis of Duchenne muscular dystrophy
creatinine kinase high
muscle biopsy - absent dystrophin
inheritance of tuberous sclerosis
autosomal dominant
genetic cause of tuberous sclerosis
most mutations on TSC2 gene on chromosome 16 ** which codes for tuberin or TSC1 gene for hamartin
—> FORMS HAMARTOMAS (organ malformations of hypertrophied abnormal mixture of cells)
——> leads to dysregulated mTOR (mammalian taaget of rapamycin)
clinical dermatology features of tuberous sclerosis
- hypomelanotic macules
- ash leaf macules
- shagreen patches
- adenoma sebaceum (acne linke)
clinical features of tuberous sclerosis
- retinal hamartomas
- dental fibromas
- cardiac rhabomyomas
- focal seizures + infantile spasms
- learning disability, ADHD, autism
- renal calculi
- cortical tubers and subependymal nodules
inheritance of friedrichs ataxia
autosomal recessive
genetic cause of friedrichs ataxia
defect in FXN gene (frataxin protein) - GAA repeat expansion in non coding region of gene coding for frataxin and causes excessive iron deposits in mitochondira
presentation of friedrichs ataxia
- progressive ataxia
- normal intelligence
- absent deep tendon reflexes
- peripheral sensory neuopathy
- dysarthria
- progressive scliosis and kyphosis
- hypertrophic cardiomyopathy
- diabetes
- optic atrophy
inheritance of neurofibromatosis type 1
autosomal dominant
50% DE NOVO mutations
genetic cause of neurofibromatosis type 1
mutation on chromosome 17
NF1 gene encodes for neurofibrin. (tumour suppressor gene) -> decreased production of neurofibrin
presentation of neurofibromatosis type 1
- cafe au lait spots
- anxillary freckling
- skeletal dysplasia
- neurofibroma
- lisch nodules (raised tan coloured hamartomas of iris)
- optic glioma
- hypertension- due to renal artery stenosis
- neuro abnormalities e.g. LD, seizures
inheritance of cystinuria
autosomal recessive
genetic cause of cystinuria
mutation in SLC3A1 gene on chromosome 2 and SLC7A9 gene on chromosome 19 - codes for transporter protein in proximal convulated tubule for amino acids - so excess urinary excretion of certain amino acids e.g. cystine, arginine, lysine, orthinine
main complication of cystinuria
causes kidney stones !!! cystine crystallizes and forms stones !!! can result in CKD !!!
present with haematuria, flank pain, N&V, recurrent UTIs, incidental finding
definitive diagnostic test of cystinuria
quantitative amino acid chromatography of urine (shows increased urine cystine levels)
cystinuria management
- high fluid intake >3L a day
- alkalising urine agent - potassium citrate
- dietary Na restriction
genetic cause of MCAD deficiency
mutation in ACADM gene which codes for MCAD leading to deficiency of enzyme so unable to metabolise medium chain fatty acids into energy
causes reduced hepatic ketogenesis
when does medium chain acyl co-enzume A dehydrogenase deficiency present
presents in times of increased energy demands normally in infancy e.g. when ill, prolonged periods of fasting
individual can not produce enough energy from fat stores which causes hypoglycaemia and metabolic crisis
presentation of MCAD deficiency
presents with at 2-3 months old:
1. hypoketotic hypoglycaemia
2. vomiting, lethargy, reduced GCS, hepatomegaly, seizures
3. recurrent infections
diagnosis of MCAD deficiency
newborn screening !!!
measures acylcarnitine levels in blood spots and shows high C6-C10 species (esp C8 - otanolycarnitine)
tests to do if suspect MACD deficiency
- glucose - low
- high ALT and deranged LFTs
- high ammonia
- high urate
- high C8 levels/ octanolycarnitine levels + high acyclcarnitine levels
- urinary amino acids
- ketones low
management of MCAD deficiency
- avoidance of fasting and regular feeding
- low fat diet
- IV glucose in times of metabolic crisis
- L carnitine supplements
inheritance of sickle cell anaemia
autosomal recessive
genetic cause of sickle cell anaemia
point mutation at position 6 on beta globin gene (glutamine -> valine) which causes formation of HbS which is rigid and insoluble.
pathophysiology of sickle cell
Hb S polymerises when in low oxygen tension and forms sickle cells.
sickle cells become trapped in microvasculature
causes thrombosis or ischaemia
presentation of sickle cell
chronic haemolytic anaemia
jaundice
increase risk of encapsulated organisms e.g. salmonella, pneumococcus
diagnosis of sickle cell
NEW BORN SCREENING
high performance liquid chromatography
chronic management of sickle cell
- folic acid
- prophylactic abx
- vaccinations
- hydroxycarbamide - increases HbF levels and reduces painful episodes
- crizanlizumab - monthly infusion, trial
acute management of sickle cell
- analgesia - morphine
- hydration. IVF
- oxygen
- transfusion
- IV antibiotics
inheritance of hereditary spherocytosis
autosomal dominant
pathophysiology of hereditary spherocytosis
- inherited defect in genes that code for erythrocyte cytoskeleton e.g. spectrin
- loss of membrane surface causing sphering of RBCs
- impaired cell passage from splenic cords to sinuses and prone to haemolysis
presentation of hereditary spherocytosis
- jaundice
- fatigue
- chronic haemolytic anaemia
- splenomegaly
- abdo pain
- gallstones
investigations for hereditary spherocytosis
- FBC, reticulocyte count
- blood film - spherocytes and reticulocytosis
- LFT - unconjugated bilirubin increase
inheritance of haemophilia
X linked recessive
haemophilia A definition
deficiency of factor VIII
more common
haemophilia b definition
deficiency of factor IX
vit K dependent
presentation of haemophilia
haematoma at delivery
excessive bleeding
unexpected bleeding loss
excessive bruising
epistaxis
intracranial bleeding
investigations for haemophilia
FBC - low haematocrit
prolonged APTT
factor VIII or IX reduced
inheritance of G6PD deficiency
X linked recessived
missense mutations
presentation of G6PD deficiency
- neonatal jaundice
- haemolytic anaemia
- drug sensitive haemolytic anaemia e.g. nitrofurantoin, quinine, aspirin, chloramphenicol
- favism - acute intracvascular haemolysis after ingestion of fava beans
investigations for G6PD deficiency
- FBC
- rise in indirect bilirubin
- rise in LDH
- smear - heinz bodies, bite cells
inheritance of cystic fibrosis
autosomal recessive
genetic defect in CF
defective CFTR (cAMP dependent Cl channel) on chromosome 7
most frequent mutation F508 - class 2 mutation causing defective protein folding so cant reach apical membrane
presentation of newborn with CF
- meconium ileus - vomiting, abdo distension, failure to pass mec
- prolonged neonatal jaundice
presentation of infant with CF
- faltering growth
- recurrent resp infections, H influenza -> pseudomonas aeruginosa -> burkholderia
- wet cough
- malabsorption, steattohoea
presentation older child with CF
- bronchiectasis
- rectal prolapse
- nasal polyp
- sinusitis
- inferity in males
- diabetes
- distal intestinal obstruction
inheritance of primary ciliary dyskinesia
autosomal recessive
pathophysiology of primary ciliary dyskinesia
defect in structure or funtion of ciliary proteins causing inefficacy of cilia - cilia beat frequency affected
presentation of primary ciliary dyskinesia
- recurrent chest infections
- productive cough
- purulent nasal discharge
- chronic ear infections
gold standard diagnostic test for primary ciliary dyskinesia
bronchial brush biospy and transmission electron microscopy
what is kartagener syndrome
- ciliary dyskinesia
- sinus vertus
- dextrocardia
inheritance of spinal muscular atrophy
autosomal recessive
features of spinal muscular atrophy
gross motor delay
lower motor neurone pathology - reduced muscle tone, absent deep tendon reflexes
diagnosis of spinal muscular atrophy
molecular genetic testing- most caused by deletion of exon 7 on SMN1 gene
features of Pendred syndome
sensorineural deafness b/l - dilated vestibular aqueducts
goitre
vestibular dysfunction
genetic cause of cri du chat
chromosome 5 p deletion
features of cri du chat
high pitched cry
feeding difficulties
low birth weight
developmental delay
dysmorphic features - down ward slanting mouth, low seat ears, small head, flat nasal bridge
features of foetal alcohol syndrome
thin vermillon border
smooth philtrum
short palpebral fissures
developmental delay
irritable
triad of wiskott aldrich syndrome
- eczema
2.thrombocytopenia - recurrent bacterial infections
X linked recessive immunodeficiency disorder
investigation for angelmans syndrome
DNA methylation testing
1st test for global developmental delay
microarray
identify chromosome imbalance, microdeletions and micro duplications
test for fragile X syndrome
FMR1 DNA anaylsis
presentation of russel silver syndrome
IUGR
triangular facies
limb asymmetry
clinodactyly
cause of myotonic dystrophy
expansion of cTG nucleotide in non coding region DPMK
describe nieman pick disease
neurodegenerative disease with defect in intracellular cholesterol trafficking
presentation of nieman pick disease
cherry red spot
vertical supranuclear gaze plasy
severe jaundice
hepatosplenomegaly
present before age of 10
describe features of non ketotic hyperglycinaemia
neonatal encephalopathy
‘hiccups’
poor feeding
apnoeas
myoclonic fits
non dysmorphic
hypotonia
normal acid base and ammonia levels
high levels of glycine
describe mucopolysaccharidosis type 1
lyososomal storage disorder by mutations in IUDA gene
failure to breakdown glycosaminoglycans (GAGs) leads to accumulation and multi organ disease
hurler syndrome = subtype
presentation of mucopolycaccharidosis type 1
normal development and then plateua and regression
reduced growth
mixing hearing impairments
recurrent upper resp tract infections
micrognathia, macroglossia
hepatosplenomegaly
corneal clouding/ opacity
short stubby fingers
test for mucopolysaccharidosis type 1
elevated urine glycosaminoglycans (GAGs)
enzyme increased in gauchers disease
acid phosphatase increased
presentation of refsums disease
chronic ataxia and peripheral neuropathy
deafness
retinitis pigmentosa
anosmia
itchy skin
cause of refsums disease
lack enzyme in peroxisosomes so phytatic acid accumulates
describe glycogen storage disorders
lack the enzyme for glycogen metabolism to glucose
causes hypoglycaemia and lactic acidosis
slowly progressive clinical picture with dysmorphic features + organomegaly + skeletal dysplasia + developmental degression
describe mcardles disease (type V glycogen storage disorder)
deficiency of enzyme phosphylase in the muscle so there is blocked breakdown of glycogen in the muscle
presentation of mcardles disease (type V glycogen storage disorder)
pain and weakness in the muscles when exercising -> relieved when exercise stopped
myopathy
investigations for mcardles disease
- lactic acidosis
- urine myoglobunuria (rhabdomyolysis)
describe pompes disease
mutation in lysosomal transport system that degrades glycogen into glucose
autosomal recessive
presentation of pompes disease (glycogen storage disorder type 2)
cardiomyopathy + heart failure
faltering growth
hypotonia
hypoglycaemia
hearing loss
large tongue
describe arginase deficiency (urea cycle disorder)
autosomal recessive
mutation in AR1 gene
elevated alanine, glutamine and arginine
present at 1-3 y/o with poor growth, developmental regression, seizures, spasticity
describe cause of ornithine transcarbamylase (urea cycle disorder)
X linked recessive
mutation in OTC gene
test results for ornithine transcarbamylase
high urine ototic acid
high alanine and high glutamine levels
low citrulline and low arginine
describe citrullinaemia
autosomal recessive
mutation in ASS7 gene
deficiency arginosuccinate synthetase so stops synthesis of arginosuccinate in cytoplasm
presentation of urea cycle disorders
newborn presentation
vomiting
encephalopathy from high ammonia levels
seizures
failure to feed
tests for urea cycle disorders
very high ammonia
resp alkalosis -> metabolic acidosis
urine for organic acids
normal glucose, normal ketones
high glutamine and alanine (nitrogen carrying amino acids)
test for tyrosinaemia
urine succanylacetone positive
presentation of tyrosinaemia
jaundice and liver damage
renal tubular injury
hypertrophic cardiomyopathy
describe homocystinuria
disorder of conversion of methionine to cysteine causing accumulation of homocysteine
presentation of homocystinuria
stiff joints
thrombosis
learning difficultues
sublexed lens -‘flashing lights’
weakness
long arm span
similar to marfans disease
describe cause of glutaric aciduria type 1 and presentation
build up of lysine, tryptophan and hydrocylysine in basal ganglia
minor illness triggers dystonic movements and regression in development
tests for maple syrup urine disease
high leucine levels
high ketones
normal blood gas
reduced neurological status
tests for organic acid disorders
severe metabolic acidosis
large anion gap
hypoglycaemia or hyperglycaemia
raised ketones **
high ammonia
describe NARP
- neuropathy
- ataxia
- retinitis pigmentosa
mitochondrial disorder - defect in ATP synthase
describe features of pendred syndrome
b/l sensorineural deafness (most common form of inherited deafness)
dilated vestibular aqueducts
mild hypothyroidism
what is VACTERL
V - vertebral e.g. hemivertebra
A- anorectal e.g. imperforate, anterior displaced
C- cardiac abnormalitie
T- tracheo oEsophageal atresia
R- Renal
L- limb problems
presentation of myotonic dystrophy
antenatal polyhydramnios
hypotonia - decreased reflxes
clubbed foot
expressionless face (SMA has normal expression)
poor swallow
triangular mouth
amino acids raised in viral gatstroenteritis
raised plasma leucine, valine and isoleucine
presentation of lesch nyhan syndrome
elevated levels of uric acid
- initial development delay and hypotonia
- becomes spasticity and jerky and increased tone in movements
- aggressive and self mutilation behaviour
