Genetics Flashcards
Frame-shift mutation
Type of insertion mutation
1 or more bases inserted, changing the way the DNA is read
Deletion mutation
deletion of a nucleotide, can lead to a non-functional protein
Missense mutation
alteration of a nucloetide sequence that converts one codon for an aminoa cid into a codon for a second amino acid
can lead to pathogenic variant or unknown significance
Nonsense mutation
changes a triplet coding for an amino acid into a termination codon, leading to a non-functional protein
Point mutation
Single nucleotide change ina DNA molecule
What can array CGH not detect
balanced chromosomal rearrangements
cant distinguish between unbalanced chromosomal rearrangements caused by different mechanisms
CHD associated with turner’s syndrome
CoA and VSD
Trisomy 13 features
patau syndrome
midline defects
- cleft palate
- ASD or VSD
- fused kidneys
- holoprosencephaly
- microphthalmia
Trisomy 18 features
edwards syndrome
- SGA
- VSD +/- valve dysplasia
- short sternum
- overriding fingers
- ‘rocker bottom feet’
- multiple choroid plexus cysts on CrUSS
Physiology of how DiGeorge syndrome affects embryology
the deletion causes a reduction in T-box transcription factor 1 (TBX1) which disrupts the development of the 3rd and 4th pharyngeal arches
williams syndrome genetic defect
microdeletion on chromosome 7q11 - encompasses the elastin gene
presentation williams syndrome
cardiac - SUPRAvalvular aortic stenosis often with peripheral pulmonary branch stenosis
periorbital fullness
wide mouth & full lips
flat nasal bridge
mental retardation
hypercalcaemia
overfriendliness/short attention span/anxiety
what is an imprinting disorder
inherited genes are expressed only from a copy inherited by one parent
causes of imprinting disorder
methylation defect
- switches off genes that are normally active or switching on genes that are normally silenced
uniparental disomy
- inheritance of borth copies of a chromosome from only 1 parent
examples of imprinting disorders
prader willi
angelman
beckwith-widemann syndrome
imprinting defects causing prader-willi syndrome
Essentially expression of only maternal copy
- MATERNAL uniparental disomy at chromosome 15q11 (SNRPN Gene mutation)
- Large deletions of the PATERNAL copy of 15q11
- Methylation defects
Presentation of prader-willi syndrome
Hypotonia
Poor feeding
Overeating»_space; obesity
Hypogonadotrophic hypogonadism
Small hands and feet
Temper tantrums
High pain tolerance
Almond shaped eyes
Thin upper lip
Imprinting defects causing angelman syndrome
Essentially expression of only paternal copy
- PATERNAL uniparental disomy at chromosome 15q11
- Large deletions of the MATERNAL copy of 15q11
- Loss of function mutations on the maternal allele of UBE3A
Presentation of angelman syndrome
developmental delay
ataxia
happy disposition phenotype
wide mouth
seizures
cause of BWS
disruption of the imprinted region on chromosome 11p15
tumour that BWS patients at higher risk of and what monitoring is done
wilms tumour
abdo US every 3m until age 7
marfans genetic defect
missense mutation in the FBN1 gene on chromosome 15q - encodes for fibrillin
neurofibromatosis type 1 genetic defect
mutation in NF1 gene on 17q11.2
pathophysiology of neurofibromatosis
NF1 gene encodes for neurofibromin - a tumour suppressor protein (RAS-GAP)
Neurofibromin most common in neurons, glial cells and schwann cells
NF1 gene defect leads to RAS hyperactivation»_space; activation of pro malignancy pathways
Criteria for NF1 diagnosis
2 or more of …
- 6x cafe au lait macules
- 2x or more neurofibromas or 1x plexiform neurofibroma
- axillary or inguinal freckling
- 2 or more lisch nodules
- distinctive bony lesion
- 1st degree relative with NF1
what are lisch nodules
raised tan coloured haematomas in the iris
diagnostic criteria for NF2
1x major or 2x minor
Major
- unilateral vestibular schwannnoma % 1st deg relative with NF1
- bilateral vestibular schwannomas
Minor
- meningioma
- schwannoma
- ependyoma
- glioma
- cataract
mutations for tuberose sclerosis
point mutations on
TSC1 - chromosome 9 - encodes for hamatin
TSC2 - chromosome 16 - encodes for tuberin
pathological consequence of TSC1 or 2 mutations
dysregulation of mTOR (mamamalian target of rapamycin)
achondroplasia mutation
AD mutation in the fibrobast growth factor receptor 3 (FGFR3) on chromosome 4
diagnostic achondroplasia features at birth
short metacarpals and phalanges
short ribs with cupped anterior end
large skull with narrow foramen magnum
cause of myotonic dystrophy
monoalleic triplet repeat expansion in DMPK gene (type 1) or CNBP gene (type 2)
associated features of myotonic dystrophy (apart from muscle weakness)
cataracts & diabetes
cause of fragile x
full expansion repeats in the CGG triplet repeat in the FMR1 gene on Chromosome Xq27.3
Inheritance of alagille syndrome
AD
genetic defect in alagille syndrome
defect in the JAG1 gene on chromosome 20
presentation of alagille syndrome
butterfly vertebrae
cholestasis
facial - broad forehead, hypertelorism, small pointed chin
anterior segment abnormalities - posterior embryotoxin
mutation in CF
CFTR gene on chromosome 7
inheritance of DMD
x linked recessive
inheritance of Rett syndrome
x linked dominant
genetic defect of rett syndrome
loss of function mutation in MECP2 gene on X chromosome
presentation of rett syndrome
exclusively females
apparently normal development then regression of skills and deceleration of head growth 6-18m
midline hand movements - shaking, inability to hold things
genetic defect in incontentia pigmenti
mutation in the NEMO gene on Xq28
inheritance of incontentia pigmenti
x linked dominant
presentation of incontentia pigmenti
affected male pregnancies most liley will miscarry
cropped circumferential blisterning lesions on the trunk with linear distribution on the limbs
lesions regress by late childhood and leave atrophic streaky areas of pigmentation
inheritance of holt-oram syndrome
AD
genetic defect in holt oram syndrome
TBX5 gene mutation on chromosome 12
presentation holt-oram syndrome
hypoplastic thumbs
ASD
absent radii
CHARGE syndrome
coloboma
heart disease
atresia (choanal)
retardation of growth
genitourinary abnormalities
ear anomalies
presentation of pierre robin
3 classic features
- cleft palate
- glossoptosis
- micrognathia
inheritance of treacher collins
AD
genetic defect in treacher collins
TCOF1 gene mutation on chromosome 5q32
pathophysiology of treacher collins
failure of neural crest cells to develop into the first pharyngeal arch in 4th week of pregnancy
presentation of treacher collins
micrognathia
malar hypoplasia
ear malformations
down slanting eyes
conductive deafness
lower eyelid coloboma
associated ocular manifestion of familial adenomatous polpyosis
congenital hypertrophy of the retinal pigment epithelium
genetic defect in hereditary spherocytosis
ANK1 gene mutation
genetic defect in cri du chat
deletion of the ‘p’ arm
inheritance of tay sachs
AR
cause of tay sach’s disease
mutation in the hexosamindase subunit alpha (HEXA) gene on chromosomal 15
pathophysiology of tay sachs
mutation > diminished levels of hexasamindase A enzyme > failure ot breakdown GM2-ganglioside > accumulation within neurones of the brain and spinal cord
inheritance of pendred syndrome
AR
presentation of prendred syndrome
bilateral sensorineural deafness
vestibular dysfunction (bilateral dilatation of the vestibular aqeducts)
goitre
Ix for pendred syndrome
MRI middle ear
inheritance of laurence-moon-biedl syndrome
AR
presentation of laurence-moon-biedl syndrome
obesity
cranial DI
hypogonadism
night blindness
retinitis pigmentosa
polydactlty
tinnitus
inheritance of cockayne syndrome
AR
presentation russell-silver syndrome
prenatal growth restriction
triangular face
5th finger clinodactlyly
cafe au lait spots
sweatiness
inheritance of noonans syndrome
AD
genetic defect in noonans syndrome
PTPN11 gene mutation on chromosome 12q
presentation noonans syndrome
short stature
hypertelorism
pulmonary stenossis
hypertrophic cardiomyopathy
pectus carinatum / pectus excavatum
mild DD
undescended testes
