Genetics Flashcards
Dravet syndrome
See neuro
West syndrome
See neuro
Rett syndrome
MEPC2
Prader Willi and Angelman
- Deletion of the region 15q11-q13 is associated with Prader-Willi and Angelman syndromes.
- This can present with poor feeding, generalised hypotonia but with otherwise normal neurological exam.
- Prader willi–> facial features such as a narrow forehead, almond-shaped eyes, and a triangular mouth; short stature; and small hands and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored hair
- -> ID usually mild. Usually need GH. Risk of obesity
–> PATERNAL copy is deleted, OR has two maternal copies, OR Paternal copy is silenced
-Angel man –> happy puppet, microcephaly, hand flapping, Severe ID, bouts of laughter, love water, poor sleep
- -> lareg mouth, large chin
- -> MATERNAL copy is deleted OR has two paternal copies OR maternal copy is silenced OR deletion of UBE3A
Williams syndrome
- Williams syndrome is caused by a deletion in chromosome 7q11.23
- can detect on microarray
- Aortic stenosis
- Joint laxity
- Hypercalcemia
Periorbital fullness, a flat nasal bridge and a broad nasal tip, a long relatively smooth philtrum with a wide mouth. The vermilion of lower lip is thick. Full cheeks and an ‘elfin’ face, which is often seen in young children with Williams syndrome.
alagille syndrome (aka arteriohepatic dysplasia)
AD
Mutation on chromosome 20p
JAG1 (90%) or NOTCH2
Variable expressivity (may have mild dysmorphism, mild cholestasis)
- Bile duct paucity of INTRAhepatic ducts
- Absence or marked reduction in the number of interlobular bile ducts in the portal triad (may initially not have these findings and instead look histologically like biliary atresia
- Chronic liver disease
- Conjugated hyperbilirubinaemia with cholestasis
- Increase lipoprotein X (++ xanthoma) and raised cholestrol
- Vit E deficiency MUST rx
- “butterfly” verterbrae
- abnormal radius/ulna
- abnormality of embryotoxin of eye
- Cardiac defects (pulmonary valve, artery and branches) –> peripheral pulmonary valve stenois
- renal failure
- Increase risk of vascular anomalies (aneurysm) especially of circle of willis
FACIES: Frontal bossing Prominent jaw with sharply pointed chin Deep set eyes Bulbous tip of nose
Goldenhar syndrome
Aka oculoauriculovertebral syndrome
incomplete development of ear, nose, soft palate, lip and mandible
anomalous development of first and second branchial arch
other features
teratoma
strabismus
preauricular skin tags
Autosomal dominant
Beckwith wiederman
Imprinting disorder 11p15 IGF2 gene Loss of maternal = paternal OVEREXPRESSION = growth promoting
Diagnosis is based on either three major features or two major plus three or more minor features.
Major:
- Pre and/or postnatal overgrowth (>90th centile),
- Macroglossia
- Abdominal wall defects.
Minor features:
-Characteristic ear signs (ear lobe creases, posterior helical pits),
-Facial naevus flammeus
-Hypoglycaemia
-Organomegaly
-Hemihypertrophy (25% of cases).
- increased risk of embryonal tumours (those with hemihypertrophy are at greatest risk)
esp wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma
-abdo USS every 3/12 until 8 years old
- big risk of neonatal hypoglycemia due to hyperplasia of islet cells –> increased insulin secretion –> needs MORE dextrose
- associated with IVF conception
- Infants are more likely to be delivered prematurely, 35% before 35 weeks. Exomphalos occurs in 50% of cases. Hypoglycaemia, which is usually mild and transient, occurs in 50% due to hyperinsulinism. Deaths that occur are usually related to prematurity or congenital cardiac defects (<10%)
- During childhood, dysmorphic features become less apparent, although macroglossia can cause feeding problems, speech problems and occasionally obstructive apnoea.
- Overgrowth is most marked in the first few years and is associated with advanced bone age. It tends to slow down in late childhood, and most adults are <97th centile.
Turner
XO
- 1/5000 live irths
- not associated with maternal age
- In 75% X lost is paternal
features: Small for age Delayed puberty webbed neck protruding ears Wide spaced nipples lymphoedema of hands and feet Short
Cardiac lesions (40%)
- usually bicuspid aortic valve
- aortic stenosis
- mitral valve prolapse
Gonadal dysgenesis
- primary amenorrhoea
- lack of secondary sex characteristics
-mental retardation in 6%
Renal issues:
Structural renal abnormalities in 60%
Treacher Collins
-autosomal dominant
- midface hypoplasia, micrognathia, ear dysplasia, deafness) amongst others. Microphthalmia.
- ADD
Friedriech ataxia
ADD
Noonans
- Noonan syndrome is usually caused by a SINGLE NUCLEOTIDE mutation in one of 14 genes including in PTNP11 (50% cases)
- Similar presentation at times to Turner’s
- CANNOT be detected on microarray
- Cardiac lesions:
- pulmonary stenosis
ADD
Charcot marie tooth
ADD
SMA
ADD
Mcune Abright
- syndrome of endocrine dysfunction associated with patchy cutaneous pigmentation and fibrous dysplasia of the skeletal system
- missense mutation in the gene encoding the α-subunit of GS
- large irregular cafe au lait called ‘coast of maine spot)
- Cutaneous pigmentation typically is most extensive on the side showing the most severe bone involvement
- precocious puberty; and numerous hyperfunctional endocrinopathies.
- The full syndrome with gonadotropin independent precocious puberty occurs only in girls
- Autonomous hyper function of many glands, caused by the missense mutation
- Polyostotic fibrous dysplasia of bone, leading to pathologic fractures. Can involve any bone but most commonly affects the long bones, ribs, and skull
- Fibrous dysplasia ranges from small asymptomatic areas detectable only by bone scan to markedly disfiguring lesions that can result in frequent pathologic fractures and impingement on vital nerves.
NF1 and NF2
ADD
Spinocerebellar ataxia
ADD
Ataxia telangectasia
ADD
can get bleeds in brain
VACTERL
Association
Usually sporadic
V- vertebral defects
A- anal atresia (and other GU defects)
C- cardiac defects (40-80%)
TE- tracheo-oesophageal fistula (40-80%)
R- Renal anomalies (50-80%) -include horseshoe, duplex, abnormal shape
L- Limb anomalies (40-50%) - including radial anomalies and hypoplastic/missing thumbs
CHARGE syndrome
CDH7 gene mutation on chromosome 8 (among other gene mutations)
C-coloboma
H- heart defects
A- atresia of chonae
R- retardation of growth and development
G- Genitourinary defects (hypospadias etc)
E- ear anomalies (bowl shaped and concaved eare = lop ears) and deafness
15-20% have Tracheo-oesophageal fistula
Russell Silver syndrome
Imprinting disorder –> methylation studies
11p15
IGF2 gene
Loss of Paternal = Maternal OVEREXPRESSION
= growth restricting
-UPD7 gene defect in 10%, the rest is loss of paternal –> SNP study
- IUGR, macrocephaly (pseudohydrocephaly), assymetry, clinodactyl of pinky finger (= much smaller)
- Often speech delay but normal IQ
- short when older
- risk of neonatal fasting hypoglycemia
Smith lemli opitz syndrome (SLOS)
- 7-dehydrocholesterol reductase deficiency
- Inborn error of cholesterol synthesis
- AR
- incidence 1/20 000–1/70 000. SLOS is more common in individuals of European heritage. Carrier frequencies of specific mutations vary widely depending on ethnic background, and for Caucasians, they are in the 1–2% range
- Born with multiple congenital abnormalities including : ◾Microcephaly ◾Ptosis ◾Micrognathia ◾Epicanthal folds ◾Capillary haemangioma of the nose ◾Syndactyly of the second and third toes ◾Low-set and posteriorly rotated ears ◾High-arched, narrow, hard palate ◾Cleft lip/pale ◾Agenesis or hypoplasia of the corpus callosum ◾Cerebellar hypoplasia ◾Increased ventricle size ◾Decreased frontal lobe size ◾Polydactyl of hands or feet ◾Short, proximally placed thumb ◾Other finger malformations ◾Syndactyly of second and third toes ◾Ambiguous or female-like male genitalia ◾Congenital heart defects ◾Renal, pulmonary, liver and eye abnormalities
-syndactyly of second and third toes is MOST common physical finding
- Can range from mild disease to lethal
- In older children with mild disease may present with other malformations, growth failure, intellectual disability, behavioural problems or autistic characteristics –> if any of these should test for SLOS
- Testing –> serum levels of 7-dehydrocholesterol reductase which will be ELEVATED (as reductase cannot convert to cholesterol
Rx: Cholestrol supplements
GLUT1 deficiency
ADD
Connexin 26
add
SNHL if homozygous
Lissencephaly
2 genes
LIS1 (most severe posteriorly)
DCX (most severe anteriorly)
These brain malformations cause severe intellectual disability, developmental delay, seizures, abnormal muscle stiffness (spasticity), weak muscle tone (hypotonia), and feeding difficulties.
LIS1
Lissencephaly - (most severe posteriorly)
missense mutation usually
NO dysmorphic features
Miller-Diekar syndrome (MDS)
Lissencephaly - (most severe posteriorly)
Contiguous deletions at 17p13.3
Dysmorphic- a prominent forehead; a sunken appearance in the middle of the face (midface hypoplasia); a small, upturned nose; low-set and abnormally shaped ears; a small jaw; and a thick upper lip.
Some individuals with this condition also grow more slowly than other children. Rarely, affected individuals will have heart or kidney malformations or an opening in the wall of the abdomen (an omphalocele)
Gardiner syndrome
FAP phenotypic spectrum (APC gene mutation chrom 5)
- AD
- Colonic polyps
- Osteomas (skull, mandible, long bones) –> most common
- Epidermyal cysts
- thyroid cancer
- pancreatic adenocarcinoma
- desmoid tumours
- CHRPE (congenital hypertrophy of retinal pigmented epithelium
Turcot syndrome
- FAP phenotypic spectrum (APC gene mutation chrom 5)
- AR
- Colonic polyps which become cancerous <30 years
- CNS tumours –> glioblastoma, medulloblastoma
Peutz Jeghers syndrome
- AD
- STK11 gene
- Lip freckling (melanosis), including oral mucosa, anus, around nose and eyes
- Gastric polyps (harmartomas)
- Increased risk of other malignancy of GI, pancreas, breast and ovary
Familial pancreatitis
ADD
SPINK1
A1AT deficiency
- Serpina 1 defect on chromosome 4 - SNP. Over 125 SNP defects identified.
- Low serum A1AT due to intracellular retention of defective protein
- Results in loss of regulation of neutrophil elastase
- -> hepatocyte destruction (Cholestatic jaundice in childhood)
- ->emphysema (adults)
- Z variant Pizz ++ associated with liver disease BUT 80% of neonates with Pizz associated cholestasis are healthy and free of chronic liver disease by age 18 years
Ix:
-Gold standard Analysis of phenotype of AAT protein (NOT level as A1AT is an acute phase protein and can be falsely elevated)
- Liver biopsy –> highly variable results
- HIDA is non-excreting (taken over by liver biopsy due to non-specific nature)
Hirschsprungs disease
RET
ADD
Wilson’s disease
ATP7B
ADD
Gilberts syndrome
UGTp81
ADD
Schwachman-Diamond syndrome
SBDS
ADD
IPEX syndrome
Immunedysregulation polyendocrinopathy enteropathy X-linked syndrome
-X-linked
-FOXP3 gene
-Most commonly manifests with early onset IDDM,
SEVERE watery diarrhoea (Known cause of Intestinal failure) often with FTT and DERMATITIS
If don’t treat most children die before the age of 2 years
HSCT only curative option
Stickler syndrome/dysplasia
AD
- mutations of genes encoding collagen type XI, II, IX
- facial features–> flat facies, mid face hypoplasia and prominent eyes
- prominent joints
- severe myopia
- cleft palate (no cleft lip)
- hypotonia
- hyperextensible joints
- mitral valve problems
- retinal detachment, cataracts
- short stature is NOT a feature
- 30-50% of Pierre robins sequence have stickler syndrome
-sx of osteoarthritis often arise in adolescence as well as SNHL
McArdle disease
-Glycogen storage disease type V and the most common type of glycogen storage disease.
- autosomal recessive disorder caused by mutations in the gene that encodes myophosphorylase, an enzyme that is essential for glycogenolysis.
- Exercise intolerance usually develops during childhood, along with pain, cramps, and fatigue in exercised muscle
Fragile X
X-linked triple repeat expansion >200 times -Xq27.3, FMR1 gene -accounts for 3% of males with mental retardation - features include: mental reatrdation autism (20-30%) ADHD (80%) anxiety (70-100%)
-dysmorphic features:
large cupped ears
elongated face
high arched palate
-other features
macro-orchidism
jointy laxity, flat feet
mitral valve prolapse
Triple repeat disorders
- Can only be detected by PCR, southern blot or similar
- Can be normal, pre mutation or full
- Anticipation often exists –> i.e Maternal in fragile X and myotonic dystrophy
Pre mutation FRAX
normal 5-40 Triplet repeats
premutation 55-200
Most people with a premutation are intellectually normal. In some cases, however, individuals with a premutation have lower than normal amounts of FMRP. As a result, they may have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression
Associated with Fragile X-associated ovarian insufficiency (women) and FXTAS (men)
FXTAS
Fragile X associated ataxia/tremor
- degeneration of the cerebellum
- characterized by problems with movement and thinking ability (cognition). FXTAS is a late-onset disorder, usually occurring after age 50, and its signs and symptoms worsen with age. This condition affects males more frequently and severely than females
- Typically intention tremors will develop first, followed a few years later by ataxia. Can often get parkinsonism symptoms and cognitive decline.
Sanger sequence
- good for SNPs
- Can’t detect triplet repeats >100 base pairs
Chromosome microarray
detects only large deletions or duplications, usually involving whole genes, and does not have the resolution to detect single nucleotide changes
VCF syndrome
- deletion in chromosome 22q11
- detect with microarray
-conotruncal cardiac defects(This includes tetralogy of Fallot, interrupted aortic arch, ventricular septal defects, vascular rings, truncus arteriosus, and PDA), thymic hypoplasia, hypocalcaemia in neonatal period, other features later in life
ADD
Menke Kinky Hair disease
- X-linked recessive, gene on chromosome Xq13
- defect in copper transport
Clinical features:
- Progressive neurodegeneration, severe mental retardation
- Seizures, hypotonia, feeding difficulties, optic atrophy
- Colourless hair, kinky & fragile
- Chubby red cheeks
- Death < 3 years
Investigations:
- Hair shaft: trichorrhexis nodosa (fractures along hair shaft); pili torti (twisted hair); monilethrix (brittle hair)
- Serum: copper (reduced); caeruloplasmin: (reduced)
Mx:
-Copper-histidine subcutaneously slows deterioration in some patients.
Li fraumeni syndrome
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer.
- linked to germline mutations of the tumor suppressor gene p53 (TP53
Li-Fraumeni syndrome is characterised by:
The wide variety of cancer types seen in affected individuals
A young age at onset of malignancies
The potential for multiple primary sites of cancer during the lifetime of affected individuals
The following 3 criteria must be met for a diagnosis of Li-Fraumeni syndrome:
A proband diagnosed with sarcoma when younger than 45 years
A first-degree relative with any cancer diagnosed when younger than 45 years
Another first-degree or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age
Osteogenesis imperfecta
- structural or quantitative defects in type 1 collagen (primary component of the extracellular matrix of bone and skin) - leads to osteoporosis
- classic OI is AUTOSOMAL DOMINANT
triad: fragile bones, blue sclerae, early deafness
TYPE 1 (mild): blue sclerae, recurrent fractures in childhood and presenile hearing loss
TYPE 2:(perinatal lethal): stillborn or death in the 1st year of life; extreme fragility of skeleton and other connective tissues, multiple intrauterine fractures of long bones; sclerae are dark blue-grey
TYPE 3 (progressive deforming): fractures from minimal trauma, heal with deformity, “popcorn” appearance of metaphyses due to disorganisation of bone matrix, rib cage flaring, scoliosis, vertebral compression, extreme short stature
type IV (moderately severe) type V (hyperplastic callus) type VI (mineralisation defect) type VII, type VIII (recessive)
Marfan syndrome
- AD
- mutations in gene encoding ECM protein fibrillin-1 (on 15q21)
- 30% are sporadic, new mutations often associated with advanced paternal age
- 1/5000 – 1/10000 births
skeletal: disproportionate overgrowth of long bones; anterior chest wall deformity; arm span >1.05 times height; reduced upper to lower segment ratio; arachynodactyly - wrist sign, thumb sign; thoracolumbar scoliosis
cardiovascular: AV valve prolapse/regurgitation - heart failure; ventricular arrhythmia, AF, SVT; aortic aneurysm and dissection
ocular: lens dislocation (occurs in 60-70% of patients); early and severe myopia; retinal detachment; early cataract
pulmonary: pneumothorax (15% of patients); pectus excavatum/scoliosis - restrictive lung disease
Hunter syndrome
-mucopolysaccharidosis II - deficiency of iduronate-2-sulfatase
- X-linked, Xq28 - IDS gene
- 80% point mutations, major deletions and rearrangements in the rest
- exclusively males, reported in females due to lyonisation (x inactivation)
- wide clinical manifestation due to marked molecular heterogeneity
-coarse facial features, short stature, dysostosis multiplex, joint stiffness, mental retardation manifest between 2 to 4 years of age
grouped skin papules, extensive Mongolian blue spot
Achondroplasia
- mutations at FGFR3 codon 380 - mutation maps to transmembrane domain of receptor - inhibits linear bone growth (fibroblast growth factor receptor 3)
- AD –> but most cases are sporadic
- Born with short limbs, long narrow trunk, large head with midfacial hypoplasia and prominent forehead (prototype chondrodysplasia)
- Limb shortening greatest in proximal segments, fingers often display trident configuration
- Infants usually display delayed motor milestones, often not walking alone until 18-24 months; related to hypotonia and mechanical difficulties
- spinal canal is stenotic - infants can experience compression at level of foramen magnum –>hypotonia, FTT, quadraparesis, central/obstructive apnoea, sudden death
Cleft lip and palatae genetics
- cleft lip AND cleft palate in combination have suggested that 70% are non-syndromic (i.e. 30% are associated with a syndrome).
- ->One well-described syndrome that can feature cleft lip and palate is Van der Woude syndrome -which is autosomal dominant and also features distinctive lower lip pits.
- Cleft lip and palate can also be seen as a consequence of amniotic band sequence. - Isolated cleft palate
- approximately 50% will not be associated with an underlying syndrome.
- Syndromes featuring isolated cleft palate include Stickler syndrome
- 22q11 deletion
- Treacher-Collins syndrome - Isolated cleft lip, where the vast majority are non-syndromic (90%)
Cornelia de lange syndrome
- Cornelia de Lange Syndrome (CdLS), often termed as Bushy Syndrome, is a genetic disorder that can lead to severe developmental anomalies.
- > 99% of cases are sporadic. Occasionally autosomal dominant pattern, according to several instances in which a usually mildly affected parent had one or more affected offspring
-Exact incidence is unknown, but it is estimated at 1 in 10,000 to 30,000.
Cornelia de Lange syndrome (CdLS) is a syndrome of multiple congenital anomalies characterised by:
Facies:
Long and/or thick eyebrows
Short nose
Concave nasal ridge and/or upturned nasal tip
Long and/or smooth philtrum
Thin upper lip vermilion and/or downturned corners of mouth
Other sx: Small prenatal and birth size / weight Small stature Microcephaly (prenatally and/or postnatally) Small hands and/or feet Short fifth finger Hirsutism psychomotor delay behavioral problems associated malformations that mainly involve the upper extremities ID
NF2
Gene on chromosome 22q. Diagnosis if one of the following occur:
- Bilateral VIII nerve acoustic neuromas (i.e. vestibular schwannomas) – this accounts for ~90%.
- Unilateral VIII nerve mass, in association with any two of: meningioma, neurofibroma, schwannoma, juvenile posterior subcapsular cataracts, glioma.
- Unilateral VIII nerve acoustic neuroma (or any two other brain/spinal tumours as above) and a first-degree relative with NF2.
-Clinical features include: cerebellar ataxia, hearing loss, facial neve palsy, headache.
Skin lesions are less common than in NF1.
NF1
Gene on chromosome 17q. Diagnosis if two or more of the following occur:
- ≥ 6 café-au-lait macules (prepubertal >5 mm, postpubertal >15 mm).
- ≥ 2 neurofibromas, or one plexiform neurofibroma.
- Freckling in the axillary or inguinal regions.
- Optic glioma.
- ≥ 2 Lisch nodules (iris hamartomas).
- Bony lesion – sphenoid dysplasia (pulsating exophthalmos), or dysplasia of a long bone cortex.
- First-degree relative with NF1, based on the above critera.
Incontenentia pigmenti
This is incontinentia pigmenti. This is typically lethal in males antenatally. - X-linked
In most patients, cutaneous manifestations are present at birth or occur within the first 2 weeks of life. The cutaneous manifestations usually appear in a characteristic, chronologic sequence.
-Other systemic manifestations, including ocular defects, CNS abnormalities, and dental abnormalities, may not be recognised until infancy or early childhood.
-Diagnostic criteria for incontinentia pigmenti have been proposed. In the absence of a family history, the presence of at least 1 major criterion is necessary. The presence of minor criteria supports the diagnosis of incontinentia pigmenti.
Major criteria are:
typical neonatal vesicular rash with eosinophilia
- typical blaschkoid hyperpigmentation on the trunk, fading in adolescence
- linear, atrophic hairless lesions.
Minor criteria are:
- dental anomalies,
- alopecia,
- wooly hair,
- abnormal nails
With a definitive family history, the presence of any major criterion strongly supports the diagnosis of incontinentia pigmenti.
Patau syndrome
- Trisomy 13
- Usually caused by non-dysjunction (advanced maternal age)
- Dx made by karyotype/microarray BUT FISH very important and normally done instead as only takes days to process and need to guide care
- often tlethal /die in utero
Key features:
- holoprosencephaly
- cleft/lip palate
- scalp defect
- cardiac defects
Survival:
- median 10 days
- 80% die by 3/12
- 90% by 1 year
- long term survivors profound cognitive disability
Edwards syndrome
- Trisomy 18 ( non-disjunction usually from advance maternal age)
- Usually dx antenatally as IUGR, abnormal maternal screening with low oestriol, PAPPA and BHCG
Testing: FISH, microarray/karyotype
Features at birth:
- overlapping fingers
- rockerbottom feet
- small for gestational age
- wizened feeatures (small palpebral fissures, microstomia
- prominent occiput
Survival:
- Often Fetal/intrauterine deathe
- median survival 14 days
- 80% die by 3/12
- 92% by 1 year
calculating carrier freq
double the square root of the disease incidence
PHACES
- PHACES syndrome is an association between large infantile hemangiomas of the face, head and/or neck and developmental defects of the eyes, heart, major arteries and brain.
- likely sporadic
P- posterior fossa abnormalities
H- haemangiomas (large and plaque like, may have multiple on face. May have subglottic haemangioma)
A- arterial lesions (dysplastic, narrow, aberrant, persisting fetal arteries). increased risk stroke
C- cardiac abnormalities (aortic arch abn, VSD)
E- eye abnormalities (persistent fetal vasculature, optic nerve hypoplasia
S- suprasternal skin abnormalities (midline sternal pits, dimples, clefts, cleft soft palate, athymia
