Genetics Flashcards
1
Q
What is the genetic abnormality in trisomy 21?
A
95% - 3 copies of the whole chromosome 21
3-4% - Robertsonian translocation with Ch 13, 14 or 15
1-2% - mosaicism
2
Q
What is considered to be the aetiology of trisomy 21?
A
Extra copy of chromosome 21
- nondisjunction during meiosis
Inc risk with increased maternal age
3
Q
Which screening tests indicate an increased risk of trisomy 21?
A
Decreased aFP
Low unconjugated estriol
Elevated hCG
Elevated inhibin levels
4
Q
What are the classical findings in trisomy 21?
A
Hypotonia Poor moro ID Brachydactyly - wide sandle gap Upslanted palpebral fissures Flat midface Full cheeks Protruding tongue Epicanthal folds Single transverse palmar crease Brushfield spots High arched palate Hypoplasia of the middle phalanx
5
Q
What are the common congenital cardiac defects in T21?
A
AVSD - endocardial cushion defect
6
Q
Which GI defects are associated with T21
A
Duodenal atresia (double bubble) Hirschprung disease
7
Q
Which glandular disorder should you annually screen for in T21?
A
Thyroid function
8
Q
A 30 year old mother with a child with T21 with three complete copies of ch21. What is her risk of having another child with T21?
A
1%
If parental 21:21 translocation, 100% risk. Mother balanced translocation risk is 10-15%
9
Q
Is trisomy 18 more common in boys or girls?
A
Girls 4:1
10
Q
What are the classic features of T18
A
Edwards: IUGR ID High forehead Microcephaly Small face / mouth Rocker bottom feet Overlapping fingers Short sternum Hypoplastic nails Structural heart defects - VSD
11
Q
Most common cause of death in T18
A
Central apnoea
12
Q
Classic features of T13
A
Patau: Midline defects - orofacial cleft - microphthalmia - postaxial polydactyly of limbs - holoprosencephaly - heart malformations - hypoplastic/absent ribs - genital anomalies - abdominal wall defects - aplasia cutis - rocker-bottom feet - clenched hands
13
Q
Describe a boy with Klinefelter syndrome?
A
47XXY
- tall
- gynaecomastia
- delayed secondary sexual characteristics
- azoospermia and small testes, infertile
14
Q
Describe a girl with Turner Syndrome
A
45XO
- short
- web neck
- hypogonadotropic hypogonadism - ovarian failure/gonadal dysgenesis
- bicuspid aortic valve
- coarctation of aorta
- swollen hands/ feet
- cubitus valgus
- shield chest
15
Q
What are the classic features of a child with 4p deletion?
A
Wolf-Hirschhorn Syndrome
- Distinctive face - hypertenorism, prominent glabella, frontal bossing, short philtrum, smallness of the jaw
- Severe growth deficiency
- microcephaly
- renal problems
- hypotonia
- congenital cardiac abnormalities
- seizures (90%)
- variable developmental delay
16
Q
What are the classic features of 5p deletion?
A
Cru-Du-Chat Syndrome
- cats cry - abnormal larynx
- moon face
- down slanting palpebral fissures
- hypotonia
- short stature
- high arched palate
- wide and flat nasal bridge
- ID - severe
- cardiac manifestations
17
Q
Classic finding in 18p deletion
A
de Grouchy syndrome
- microcephaly
- developmental delay
- narrowed ear canals
- froglike position
- depressed midface
- protruding mandible
- deep set eyes
- everted lower lip (carp like)
- ID
18
Q
Which deletion syndrome is associated with trigonocephaly?
A
9p deletion (triangle head)
19
Q
Describe Angelman and the genetic mutation that caused it?
A
Ch 15
Uniparental disomy - paternal
Maternal deletion
Happy puppet, jerky ataxic movements Inappropriate laughter Microcephaly Characteristic gait Hypotonia Fair hair Midface hypoplasia Large chin/mandible Seizures Severe ID Absent / severely delayed speech
20
Q
Describe Prader-Willi syndrome and mutation
A
Ch 15
Uniparental disomy - maternal
Deletion of paternal
Infancy
- severe hypotonia and feeding difficulties
Childhood
- hyperphagia, obesity
- short stature
- small hands / feet
- hypogonadism
- mild intellectual disability
- behaviour disorders
21
Q
Describe child with Williams syndrome
A
Ch 7 microdeletion (elastin defect) Cocktail personality Broad forehead Elfin facies Stellate pattern of iris Supravalvular aortic stenosis ID Hypercalcaemia Joint laxity Growth delay / short stature
22
Q
What characterises WAGR syndrome?
A
Wilms tumour
Aniridia
Genitourinary malformations - male
Mental retardation
23
Q
Describe the classic features of Alagille syndrome. What are the most common cardiac manifestations?
A
AD inheritance, JAG1 gene Triangular face, pointed chin Long nose, broad midface Bile duct paucity with cholestasis - presents first 3/12 with cholestasis, jaundice, pruritus Peripheral pulmonary stenosis, PV stenosis Ocular defects - posterior emrbryotoxon Butterfly vertebrae
Cardiac:List
Peripheral and branch pulm stenosis (67%)
Tetralogy of fallot
24
Q
List common findings in 22q11.2 deletion syndrome
A
CATCH22 Cleft palate Absent thymus Congenital heart disease - TOF>interrupted aortic arch>VSD>truncus arteriosus
Short stature
Behaviour problems
Hypocalcaemia - absent parathyroid gland
ID
Diagnosis with FISH / microarray
25
Differentiate AD pedigree
Mutation in 1 gene only
Both sexes equally affected
Both sexes transmit to offspring
Present in all generations
Every affected child has a parent with the disorder
Fathers can transmit to sons (this excludes XLR and mitochondrial)
High spontaneous mutation
26
Differentiate AR pedigree
Only disease phenotype when both alleles carry mutations
No history of disease in prior generations
Males and females equally affected
Males and females can each transmit the altered allele
Risk for 2 heterozygotes is 1/4
Consanguinity increases risk
27
Differentiate X-linked pedigree
Dominant or recessive
Recessive - more common, mostly affects males
Never male to male transmission
If a generation has only females, will appear to skip generation
Affected father transmits to all daughters and no sons
Carrier females have 50% change of transmitting disease to each son
28
What is germline mutation?
Parent carries the gene mutation in gonadal tissue and germline cells, but not in somatic cells - so no signs of disease.
Future offspring are at increased risk to inherit condition
29
Which form of classic Mendelian inheritance does not have male-male transmission?
X linked disorders
30
Which form has father passing to all daughters and no sons
X linked disorders
31
What is an example of genetic imprinting?
Differences in gene expression depending if disease inherited from father or mother
Angelman - maternal deletion
Prader-Willi - paternal deletion
32
How is mitochondrial inheritance unique?
Egg, not sperm, tramsits all mitochondria
Mother passes to all children
Father does not pass it on
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Myoclonic epilepsy and ragged-red-fibres
Mitochondrial encephalopathy, lactic acidosis, stroke like episodes
Leigh syndrome (basal ganglia defects, hypotonia, optic atrophy in infancy/early childhood)
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33
Are dizygotic twins more likely, less likely or equally likely to have traits similar to those of a nontwin sibling?
Dizygotic twins are no more similar than nontwin siblings
34
Name 4 diseases or abnormalities that are more likely to be concordant in monozygotic than dizygotic twins?
Autism 60% mono, 0% di
Cleft lip/palate 38% vs 8%
Clubfoot 32% vs 3%
Spina bifida 72% vs 33%
35
A positive prenatal quad screen indicates an increased risk of what 4 disorders? (aFP, bHCG, estriol and inhibi A)
T21, T18, neural tube defects, abdo wall defects
36
What diagnostic testing method is used to detect single gene defects?
Sanger method
37
Chromosomal instability syndromes most commonly have what pattern of inheritance?
Largely autosomal recessive
Increased freq of chromosomal breaks
eg. ataxia telangiectasia, Bloom syndrome, Fanconi syndrome, xeroderma pigmentosum
38
What is Pierre Robin sequence?
Mandibular hypoplasia
Displacement of tongue -> U shaped cleft -> displacement of tongue into the airway -> resp distress and feeding problems
No macroglossia!
39
Anomalies in hemifacial microsomia
External ear anomilies - microtia, anotia, canal atrasia
Maxillary and/or mandidular hypoplasia
Cervical vertebral anomalies 33%
Renal 15%
Goldenhar = hemifacial microsomia with epibulbar lipodermoids, VSD
40
What type of head growth is seen with early closure of the sagittal sutures?
Excessive anterior/posterior growth
Long, narrow head , occipital prominence
Dolichocephaly
41
What type of head growth is seen with early closure of the coronal and sphenofrontal sutures?
Unilateral flattening of forehead
Elevation of ipsilateral orbit and eyebrow
Prominent ear on affected side
Frontal plagiocephaly
42
What type of head growth is seen with early closure of the metopic sutures?
Keel shaped forehead and hypotelorism
| Trigonocephaly
43
What is positional plagiocephaly?
Postnatal flattening of the skull - caused by infant's preference of sleeping/resting position
44
Describe findings in achondroplasia
Autosomal dominant! most de novo mutation FGFR3 (fibroblast growth factor receptor 3) on Ch 4p16.3
Disproportionately short stature
Rhizomelic shortening
Lumbar lordosis
Trident hands
Macrocephaly
Characteristic craniofacial findings, flat nasal bridge, prominent forehead (frontal bossing) and midface hypoplasia
45
What is brachio-oto-renal syndrome?
```
AD inheritance
Brachial cleft fistulas
Preauricula pits
Cochlear and stapes malformation
Mixed conductive/sensorineural hearing loss
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46
What is rhizomelic shortening?
Short lengths of most proximal "root" segment of upper arms and legs compared to distal segments
47
What skull structural abnormality can occur in infants with achondroplasia?
Foramen mangum stenosus and/or craniocervical junction abnormalities
Compression of upper cord - apnoea, quadriparesis, growth delay, hydrocephalus
48
What is the most commonly affected bone in Caffey disease ?
Mandible - 95% of cases (helps differentiate NAI)
Infantile cortical hyperostosis, AD, incomplete penetrance
Irritability, fever, anotexia, soft tissue swelling
49
Describe a child with osteogenesis imperfecta type 1
OI Type 1: classic nondeforming OI with blue sclerae
AD - brittle bone disease
Mildest form, most common
Decrease synthesis of Type 1 collagen
```
Multiple fractures - before puberty
Blue sclerae
Delayed fontanella closure
Hyperextendable joints
Hearing loss
decreased stature
Dentinogenesis imperfecta - discoloured, weak teeth
Osteopenia long bones
Wormian dones (multiple small bones in cranial sutures)
```
50
Which type of osteogenesis imperfecta is the most severe and usually results in death in infancy?
OI Type 2 = perinatally lethal OI
Type 2 = most severe
Respiratory insufficiency = death in infancy
De novo AD mutation of COL1A1 - no normal function of Type 1 collagen
51
Which type of osteogenesis imperfecta has the highest risk of neurologic complications?
OI Type 3 = progressively deforming OI
Type 3 - hydrocephalus and basilar skull invagination
Present as newborn - multiple fractures
52
What are the classic scleral findings in osteogenesis imperfecta type 4?
OI Type 4 = common variable OI with normal sclerae
Milder form
White / near white sclerae
Tibial bowing = hallmark
53
What causes the most deaths in Marfan syndrome?
Cardiovascular complications, aortic root dilatation and rupture
Dx criteria:
Ectopia lensis (upward)
Aortic dilatation or dissection
FHx
54
Describe the typical findings in classic Ehlers-Danlos syndrome
```
AD, connective tissue disorders
Hyperextensible skin
Hypermobile joints
Easy bruising - normal coags
Dystrophic scarring
```
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Skin:
Texture - doughy, wet chamois, fine sponge
Extra on hands/feet/stomach
Stretchy like rubber band
Fragile skin
Bruising
Wrinkled palms/soles
```
MV prolapse
Proximal aortic root dilatation
55
What are the classic skin findings in NF1?
Cafe au lait spots (6 or more, >5mm prepub, >15mm post pub)
Neurofibromas >2 (or >1 plexiform neurofibroma - of peripheral nerve)
Lisch nodules - benign iris hamartoma 75% prepub
56
How frequently is NF1 due to a new mutation?
50% are sporadic, or de novo AD mutations
57
Describe how NF2 differs from NF1
AD disorder
Essentially no clinical overlap with NF1
Bilateral vestibular schwannomas (acoustic neuromas)
58
What abnormalities do vestibular schwannomas cause in NF2?
- SNHL
- tinnitus
- imbalance
- facial weakness
59
Describe the skin findings in tuberous sclerosis
Hypopigmented macules (ash leaf spots) - 90%
Shagreen patches - oval nevoid plaque on trunk/lower back
Facial angiofibromas
Forehead plaques
Nail / gingival fibromas
60
What cardiac tumours are common in infants with tuberous sclerosis?
Cardiac rhabdomyosarcomas - 50% infants
Infantile spasms also common in TS - treat with vigabatrin
61
What tumours are commonly seen in patients with von Hippel-Lindau syndrome?
Cerebellar hemangioblastoma in adolescence
OR
Retinal angioma by 10yo
Mutation VHL tumor supressor gene Ch3
62
Noonan syndrome has what type of inheritance pattern?
Autosomal dominant
63
Beckwith-Wiedemann syndrome has what type of inheritance pattern?
Autosomal dominant 11p15.5 deletion
64
What are the features of Beckwith-Wiedemann syndrome?
```
LGA
Generalised overgrowth
Macroglossia
Ear lobe creases
Posterior auricular pits
Omphalocele
Wilms tumour
Cryptochidism
Hemihypertrophy
```
65
What syndromes have cafe au lait spots?
NF1
McCune Albright Syndrome
Russell-Silver
