Genetics - single gene disorders

Question 1

Cornelia De Lange - genetics, features

Answer 1

Single gene mutation: NIPBL = 60%, SMC1A = 5%, Other = RAD21, SMC3, HDAC8
Most commonly AD, usually de novo, risk to siblings 1.5% due to possible germline mutation
Severe intellectual disability + microcephaly, poor growth (<5th centile prenatal onward)
Dysmorphism: short nose, long philtrum, unibrown (synophrys), arched eye brows, long eyelashes, hirsutism, cleft palate, low set ears
MSK: ulnar ray defects, clinodactyly, 2nd-3rd toe syndactyly
Severe GOR
ASD/self-destructive tendencies, infertility, hearing/visual impairment
Cardiovascular= PS, VSD, ASD, coarctation

Question 2

Noonan - genetics, features

Answer 2

AD – 2/3 de novo mutation
PTPN11 (50%) encodes SHP2 phosphatase, interrupts Ras-MAPK
Other genes involved: KRAS, SOS and RAF1
Face: low set ears, blue/green irises, hypertelorism, down slanted eyes with epicanthal folds, ptosis
Short stature, broad/webbed neck, superior pectus carinatum, inferior pectus excavatum, wide-spaced nipples
CHD: PVS, ASD, HOCM
Cryptorchidism in males
Developmental delay
Haematological: coag defects, JMML

Question 3

Costello - genetics, features

Answer 3

AD - usually de novo. HRAS mutation (missense, causes defect in Ras/MAPK pathway)
FTT = due to severe postnatal feeding difficulties; Developmental delay or ID
Short stature, coarse facial features full lips, large mouth, full nasal tip, curly/sparse fine hair, loose soft skin with deep creases, facial and perianal papillomata
Diffuse hypotonia and joint laxity, tight Achilles, hand in ulnar deviation
Cardiac: HOCM, PS, arrythmia
10-15% tumour risk: rhabdo, ganglioneuro, bladder. USS 3/12 until 6-8yo.

Question 4

Cardiofaciocutaneous Syndrome

Answer 4

AD, de novo, 4 genes: BRAF, MAP2K1, MAP2K2, KRAS
FTT, DD, seizures, HOCM, PS, other valves/septal defects, arrhythmia, risk of ALL
Tall forehead, low ears, sparse curly hair, flat nasal bridge
Xerosis (v dry skin), hyperkeratosis, dystrophic nails

Question 5

Sotos Syndrome

Answer 5

AD, NSD1 mutation - >95% de novo (deletion/point mutation); risk to siblings <1%
Facial features: broad prominent forehead + large head, sparse frontotemporal hair (high anterior + temporal), down slanting palpebral fissures, malar flushing, long and narrow face, long/pointed chin
Learning disability, DD, behaviour problems, mild-severe ID
Overgrowth - height/HC >2SD above mean, may normalise in adulthood but macrocephaly usually persists
Advanced bone age, joint hyperlaxity, pes planus
Cardiac and renal anomalies, rcoliosis, seizures