Genetics

Question 1

Marfan Syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 1

1) “Tall and stretchy”: disproportionate tall stature, joint laxity, lens dislocation (upward), aortic root dilatation
2) Connective tissue disorder: tall, long limbs, thin, arachnodactyly, chest wall deformity, hypermobile joints, aortic dilation/regurg/dissection, MR, ectopia lentis (50-80%)
3) Autosomal dominant, broad phenotype, 1:4000, single gene disorder FBN1 mutations
4) Single gene FBN1 sequencing or aortopathy panel
5) Dissections treat with ARBs/beta-blockers, screen 1st degree relatives, pneumothoraces

Question 2

Cystic Fibrosis

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 2

1)

2)

Question 3

Trisomy 21

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 3

1) Hypotonia, facial/physical features (upslanting palpebral fisures, low set ears, short neck, etc), 50% CHD
2) Prenatal: increased nuchal/absent nasal bone, Birth: dysmophrism/hypotonia/malformations
3) 1:800, 95% trisomy, 2.5% translocation, 2.5% mosaic
4) Karyotype, microarray, FISH
5) Hypothyrodism, Congenital heart disease (VSD), Leukaemia, Sleep apnoea, Hearing loss, Alzheimer’s, GIT (duodenal atresia, hirschprungs, TOF)

Question 4

Kleinfelter syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 4

1) Eunochoid body Habitus
2) Hypogonadism: less muscular, small testes, small penis, gynaecomatstia, pubertal delay, underdevelopment 2ndary sec characteristics (body hair), low IQ, behavioural problems (impulsive, poor attention, poor judgement, lack insight)
3) 47XXY, non-disjunctional during meiotic division
4) Karyotype, microarray, FISH
5) Diabetes, hypothyroidism, osteoporosis, breast cancer

Question 5

22q11. 2 deletion or duplication (Velocardiofacial syndrome (VCFS), di George)
1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 5

1) Result from failure of development of 3rd and 4th branchial arches -> CATCH22 (Cardiac, abn facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia, 22q11.2)
2) Neonate with congenital abns or older child with developmental delay/short stature, wide phenotypic variation
- > Micrognathia, low-set/square ears, asymmetric crying face
3) Heterozygous microdeletion at 22q11.2
4) MA, FISH, need to check parents
5) 20% autism, 60% psychiatric illness (SCZ 25%), variable immune function (test prior to live vaccines)

Question 6

Turner’s syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 6

1) Short stature, aortic coarctation, primary ovarian failure
2) congenital lymphoedema (puffy hands/feet at birth), heart shaped face, webbed neck, shield chest, wide spaced nipples, nail hypoplasia, 40% CHD (aortic disection, bicuspid AV, coarct), 50% Renal (horseshoe kidney), gonadal dysgenesis
3) 45XO, in 50%, 25% mosaic, 25% other, 1:5000 (majority miscarry)
4) Karyotype, microarray, FISH
5) Hypothyroidism, Coeliac, aortic dissection, need for oestrogen treatment (1/3 spontaneous puberty)

Question 7

Trisomy 13 (Patau Syndrome)

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 7

1) Midline abnormalities: Holoprosencephaly, cleft lip/palate, heart abnormalities, scalp defect
2) Often multiple malformations in neonatal period
3) T13, nondisjunction event (adv. Maternal age), rarely translocation
4) Karyotype/microarray/FISH
5) Medium survival 10 days, 80% die by 3/12, 92% by 1 year, profound ID in long-term survivors

Question 8

Trisomy 18 (Edwards Syndrome)

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 8

1) IUGR, wizened features (small palpebral fissures and microstomia), prominent occiput, overlapping fingers, rockerbottom feet, multiple malformations
2) Prenatally: IUGR/abnormal maternal serum screening (low oestriol, PAPPA and beta-HCG). Birth: IUGR/dysmorphisms/malformations
3) T18, nondisjunction event most commonly (AMA)
4) Karyotype/microarray/FISH
5) FDIU, median 14 days, 80% die by 3/12, 92% by 1yr

Question 9

Williams

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 9

1) ‘Elfin facies’, supravalvular aortic stenosis (SVAS), ‘cocktail personality’
2) Irritable infant, child with short stature and dev delay. Specific behaviour profile: overfriendliness, social disinhibition, excessive empathy, attention problems, non-social anxiety
3) Heterozygous microdeletion on 7q
4) Microarray/FISH
5) Dysmorphism: puffy eyes (peri-orbital fullness), long philtrum, upturned nose, stellate (usually blue) iris, small widely spaced teeth
a. Mild ID (discordant verbal and nonverbal skill)
b. Complications: endocrine (hypothyroidism, hypercalcaemia) increased risk of hypertension, SVAS, joint laxity in infancy ->arthritis

Question 10

Prader Willi syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 10

1) Neonatal hypotonia (poor feeding/suck), undescended tests, hyperphagia after infancy, ID, obesity, hypopigmentation, small hands and feet
2) H2O: Hypotonia (&poor feeding), Hyperphagia, Obesity
3) Imprinting defect at 15q: loss of paternally active genes (paternal deletion, maternal UPD), not inherited
4) Methylation testing 15q, microarray abnormal in all deletion cases and some uPD
5) Risk of obesity, GH widely used, ID usually middle, behavioural issues (skin pricking)

Question 11

Angelman syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 11

1) Microcephaly, ID with absent speech, ‘happy puppets’: hand flapping, ataxia, bouts of spontaneous laughter
2) “Happy puppets”: no speech, bouts of laughter, hand flapping, ataxia
3) Imprinting defect 15q: loss of maternally active gene (maternal deletion, paternal UPD, abnormal imprinting)
4) Methylation testing 15q11.2-q13 (abn in 70%), UBE3A single gene sequencing (10%) (20% other phenocopies)
5) Severe ID, behavioural phenotype (love water, poor sleep), seizures (characteristic EEG: runs of high amplitude delta activity with intermittent spike and slow-wave discharges), monitor for obesity

Question 12

Beckwith-Widemann syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 12

1) Overgrowth (macrosomia, macroglossia, hemihypertrophy, visceromagaly), anterior abdo wall defects (omphalocele, umbilical hernia), ears (anterior lobe creases, posterior helix pits), naevus flammeus, asymmetry, hemihypertrophy
2) Neonate: macrosomia, hypoglycaemia, exophalos
3) Abnormal imprinting at 11p15, overactivity of IGF-2 gene (loss of maternal 11p): 85% sporadic 15% inherited
a. 50% loss of methylation at mat IC2 on 11p
b. 20% paternal UPD
c. 5% gain of methylation at mat IC1 on 11p
d. 5-10% CDKN1c mutations
4) Methylation testing 11p, (SNP array is abnormal in rare microdeletions/duplications and some patUPD11)
5) Complications: predisposed to embryonal malignancies (risk greatest to 8yo): Wilms, rhabdomyosarcoma, neuroblastoma, hepatoblastoma abdo US 3/12 to 8yr. Screening stratified to (epi)genotype)

Question 13

Russel-Silver syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 13

1) IUGR and postnatal short stature with macrocephaly, asymmetry, CAL spots and clinodactyly, triangular face
2) 5 features: 1. birth weight ≤ -2SD from mean, 2. Poor postnatal growth ≤ -2SD from mean, 3. Preservation of occipitofrontal head circumference, 4. Classic facial features, 5. Skeletal asymmetry
3) Heterogenous: 50-60% 11p methylation defect, <10% maternal UPD7, rest unknown (methylation defect turning off IGF02 gene – loss of paternal 11p)
4) Methylation testing 11p, if normal then UPD7 studies (DNA from parents). May detect UPD7 on SPN array
5) Risk of fasting hypoglycaemia in infancy

Question 14

Cornelia de Lange syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 14

1) IUGR, hirsutism, ulnar ray defects, severe GOR, often severe ID (mean IQ 50) with autistic traits
2) Face: short nose, long philtrum, synophrys (unibrow), arched eyebrows, long eyelashes
3) Single gene disorder: mutation in NIPBL in 2/3, RAD21, SMC3, SMC1A (XL), HDAC8 (XL)
4) Clinical exome or panel including NIPBL, SMC1A, SMC3, HDAC8, RAD21
5) Neonatal IUGR, ID and obesity, classic patients have severe ID

Question 15

Noonan syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 15

1) Short stature, webbed neck, pulmonary valve stenosis (PVS), developmental delay
2) Dysmorphism: downslanting palpebral fissures, hypertelorism, lowset posteriorly rotated ears, short webbed neck, chest wall deformity (pectus carinatum at top, excavatum at bottom), cryptorchidism
3) Autosomal dominant, single gene disorder of RASMAPK pathway: multiple genes, PTN11 and others
4) Noonan gene panel, or clinical exome
5) Complications: small excess risk of bleeding disorders, small risk leukaemia

Question 16

Sotos syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 16

1) Overgrowth, advanced bone age, high anterior and temporal hairline, long face, pointed chin, tall stature, large head
2) 4-10 yo: overgrowth (height and/or HC >2SD), facial gestalt (high bossed forehead, sparse frontotemproal hair, long narrow face, downslanting palpebral fissures, prominent jaw), mild ID
3) NSD1 mutations (>95% de novo): 10% deletions (MA), 90% point mutations
4) Microarray (10%), clinical exome with overgrowth panel applied
5) ID, good quality of life, adult height variable

Question 17

Homocystinuria

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 17

1) “Tall and stiff”: tall stature with long limbs, intellectual disability, ectopia lentis (down) +/- severe myopia
2) ID and tall stature
3) Autosomal recessive metabolic condition (mutations in both copies of CBS gene)
4) Plasma total homocysteine (most forms detected on NBST)
5) Can’t process certain amino acids accumulate homocysteine, treat protein and methionine-restricted diet, folate/B12 supplementation. Complications: thromboembolisms, seizures

Question 18

Alagille syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 18

1) Intrahepatic biliary dysgenesis, butterfly vertebrae, pulmonary stenosis, posterior embrytoxon
2) Neonate: cholestatic jaundice, bile duct paucity, renal dx (structural abn/functional 40%
3) Single gene disorder: JAG1 deletion (10%) or point mutation 30-50% de novo (NOTCH2 1-2%)
4) Microarray 10%, exome with JAG1 and NOTCH2 analysis
5) Dysmorphism: triangular face, deep set eyes, prominent jaw. Complications: mortality 10% - liver, cardiac

Question 19

Osteogenesis Imperfecta

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 19

1) Brittle bone disease: fractures with minimal or no trauma
2) Prenatally with short long bones, or childhood with multiple fractures, associated dental abnormalities (dentogenesis imperfect). Hearing loss, blue sclerae, osteoporosis, wormian bones
3) Single gene disorders of gene encoding collagen proteins: COL1A1 (most common), COL1A2, most autosomal dominant. If de novo, gonadal mosaicism risk 3-5%. Broad phenotypic severity
4) Exome with OI gene panel analysis or OI gene panel
5) Osteopenia, easy fractures, short stature, scoliosis, ligamentous laxity, easy bruising. Treatment with bisphosphonates

Question 20

Achondroplasia

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 20

1) Short stature, disproportionate short limbs
2) Prenatal or neonatal presentation: short long bones, hypotonia, gross motor delay but normal IQ
3) Autosomal dominant, single gene disorder FGFR3 mutations
4) Single gene sequencing FGFR3 (diagnostic test: skeletal survey, not gene testing)
5) Dysmorpholgoy: Macrocephaly, flat nasal bridge, trident hand, normal trunk with rhizomelic limb shortening. Complications: stenotic spinal canal (hydrocephalus, foramen magnum compression, lumbar canal stenosis), obstructive sleep apnoea, middle ear disease

Question 21

Fragile X

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 21

1) ID, developmental delay, autistic traits, large ears, large testes, long face, lax joints
2) 2-4 yo: dev delay, ID (IQ 30-50), behaviour (ADHD, autistic traits, impulsive, shy, anxious)
3) X-linked triplet repeat disorder, (female mild phenotype)
4) Fragile X testing: sizing of triplet repeat: PCR/southern blot
5) Complications: MVP, aortic root dilatation, autism 25%, seizures 20%

Question 22

Fetal Alcohol Syndrome

1) Key features
2) Clinical presentation
3) Genetics
4) Genetic Tests
5) Complications

Answer 22

1) F: face (dysmorphic features) – short palpebral fissures, flat philtrum, thin upper lip. A: abnormal learning (CNS impairment) – jittery infants, learning disability/developmental delay. S: short (poor growth) – IUGR, microcephaly, short stature
2) Criteria: 3 facial abnormalities (smooth philtrum, thin vermillion border, small palpebral fissure), growth deficits, CNS abnormality (structural or functional)
3) -
4) -
5) Complications: seizures