Genetics 1.5 Flashcards
Genetic technique that detects DNA?
Southern blotting
SNoW DRoP
Genetic technique that detects RNA?
Northern blotting
SNoW DRoP
Genetic technique that detects proteins? Example?
Western blotting
SNoW DRoP
e.g. confirmatory HIV test
Genetic technique that detects Ag & Ab?
Example?
ELISA
e.g. initial HIV test
Colour-changing enzyme attached to Ab, changes colour if Ag is detected. Enzyme attached to Ag if vice versa
2 complicating factors of Autosomal dominant inheritance?
- Non-penetrance (normal phenotype i.e. no Sx/Sx despite abnormal gene) e.g. 40% otosclerosis
- Spontaneous mutation (in one gamete e.g. 80% people with achondroplasia have unaffected parents)
Commonest congenital infection in UK
CMV
Characteristic features of Rubella?
(eyes, ears, heart)
Other features?
- congenital cataracts, glaucoma
- sensorineural deafness
- congenital heart disease e.g. PDA
Others: growth retardation, hepatosplenomegaly, skin purport, salt & pepper chorioretinitis, microphthalmia, cerebral palsy
Types of Acyanotic congenital heart disease
VSD (most prevalent) ASD (present later, Dx in adults) PDA coarctation of Aorta Aortic valve stenosis
Types of Cyanotic congenital heart disease
Tetralogy of fallot (commonest, present 1-2months)
Transposition of GA (present at birth so commoner then)
Tricuspid atresia
Pulmonary stenosis if severe
Conditions with X-linked Dominant inheritance
ARD
Alport’s syndrome (10-15% auto recessive)
Rett syndrome
Vitamin D resistant rickets
Who is affected in X linked recessive conditions?
Exception to this?
Who are the carriers?
Males are affected
Turner’s syndrome only one X chromosome therefore will be affected
Heterozygous females are carriers, unaffected. There male children have 50% chance of inheriting the gene therefore 50% chance of being affected
Genetics of William’s syndrome
Neurodeveopmental disorder caused by a micro deletion on chromosome 7
(contains elastin gene)
Features of William’s syndrome
neuro, development, biochem, heart
LD, friendly & social
Short stature, elif-like facies
Transient neonatal high Ca++
Supravalvular aortic stenosis
Dx William’s syndrome
FISH studies
fluorescent in-situ hybridisation
Genetics of Turner’s syndrome
Chromosomal disorder in 1/2500 females
1 sex chromosome or
deletion of short arm of 1 of the X chromosomes
(45, X or 45, XO)
Features of Turner’s syndrome?
heart, gynae, development, skin, autoimmune
- bicuspid aortic valve (15%), coarctation aorta (5-10)
- 1ry amenorrhoea
- webbed neck, short stature, shield chest, widely spaced nipples, high-arched palate, short 4th metacarpal
- neonatal feet lymphoedema, cystic hygroma, multiple pigmented naevi
- Inc incidence of AI disease esp thyroiditis, & Crohn’s
What are tumour suppressor genes
Normally control cell cycle
Loss of function = inc risk cancer
BOTH alleles mutated before cancer occurs
p53 - which chromosome?
ass cancers?
role in cell cycle?
- chr 17p
- many cancers e.g. breast, colon, lung
Li-Fraumeni syndrome - prevents entry into S phase until DNA has been checked & repaired; also regulator of apoptosis
APC ass cancer
colorectal
Rb ass cancer
retinoblastoma
WT1 ass cancer
Wilm’s tumour
MTS-1, p16 ass cancer
melanoma
Genetics of Prader-Willi syndrome
Genetic imprinting (phenotype depends if deletion occurs on gene inherited from father) Absence of gene on long arm chr 15 - micro deletion of paternal 15q11-13 in 70%, - maternal uniparental disomy of chr 15
Features of Prader-Willi syndrome
neurodevelopment, fert
hypotonia, dysmorphic features, short stature, childhood obesity, adolescence behavioural problems, LD
hypogonadism & infertility
Genetics of phenylketonuria
- autosomal recessive disorder of phenylalanine metabolism
- usually defect in phenylalanine hydroxylase on chr 12 (converts phenylalanine to tyrosine)
Features of phenylketonuria
High levels of phenylalanine lead to:
- developmental delay, classically fair hair, blue eyes
- LD, seizures/infantile spasms
- eczema, ‘musty’ odour (phenyl acetate)
Dx phenylketonuria
Guthrie test
hyperphenylalaninaemia
phenylpyruvic acid in urine
What is PCR
Molecular genetic technique: sample DNA strand, 2 DNA oligonucleotide primers needed, complimentary to specific DNA sequences at either end of target DNA
- 1 strand of sample DNA + 2 DNA primers + Taq (thermostable DNA polymerase)
- heated -> denaturing = uncoiling of DNA -> cooled -> complimentary DNA strands pair (XS primer sequences pair with DNA preferentially) -> repeat cycle -> DNA doubles
Reverse transcriptase PCR
- amplifies RNA
- reverse transcriptase converts RNA -> DNA
- gene expression in the form of mRNA is analysed
What is Li-Fraumeni syndrome
rare autosomal dominant
early onset of variety of cancers e.g. sarcomas, breast ca
p53 mutation
3 processes by which photo-oncogenes (inv in cell growth & differentiation) becomes oncogenes?
- mutation (point)
- chromosomal translocation
- increased protein expression
ABL is what cat of oncogene? ass cancer?
cytoplasmic tyrosine kinase
CML
c-MYC is what cat of oncogene? ass cancer?
transcription factor
Burkitt’s lymphoma
n-MYC is what cat of oncogene? ass cancer?
transcription factor
neuroblastoma
BCL-2 is what cat of oncogene? ass cancer?
apoptosis regulator protein
follicular lymphoma
RET is what cat of oncogene? ass cancer?
tyrosine kinase receptor
MEN II & III
RAS is what cat of oncogene? ass cancer?
G-protein
many esp pancRAS
erb-B2 (HER2/neu) is what cat of oncogene? ass cancer?
tyrosine kinase receptor
breast & ovarian
Genetics of Noonan’s syndrome
autosomal dominant ass with normal karyotype
defect on chr 12
Features of Noonan’s syndrome
turner’s, heart, face, blood
- webbed neck, wide nipples, short stature, pectus carinatum/excavatum
- pulmonary stenosis
- triangle face, low-set ears, ptosis
- coat problems e.g. factor XI deficiency
dsDNA in mitochondria
encodes protein components of respiratory chain & some special types of rna
histology in mitochondrial disease
muscle biopsy shows RED RAGGED fibres due to inc no of mitochondria
mitochondrial disease inheritance? who WILL get the disease? who will NOT get the disease? what is heteroplasmy?
- maternal line of inheritance (sperm doesn’t contribute cytoplasm to zygote)
- all children of affected females inherit
- all children of affected males do NOT inherit
- heteroplasmy: within tissue/cell there can be different mitochondrial populations. this is why there is poor genotype:phenotype correlation
features of McCune-Albright syndrome
precocious puberty
cafe au last spots
polyostotic fibrous dysplasia
short stature
Genetics of homocystinuria
rare autosomal recessive disease
- cystathionine beta synthase deficiency
- accumulation of homocysteine (then oxidised to homocystine)
Dx of homocystinuria
cyanide-nitroprusside test (also +ve in cystinuria)
Rx for homocystinuria
vitamin B6 (pyridoxine)
Features of homocystinuria
skin/hair, msk, neuro, eye, blood
- fine fair hair, malar flush, livedo reticularis
- similar to Marfans
- may have LD, seizures
- downwards/inferonasal lens dislocation
- increase risk arterial & VTE
Genetics of Fragile X syndrome?
trinucleotide repeat disorder
Dx of Fragile X syndrome?
- antenatal: chorionic villus sampling or amniocentesis
- analysis of no of CGG repeats using restriction endonuclease digestion and Southern blot analysis
Features in Fragile X syndrome?
Female: range normal - mild (1 fragile 1 normal X chr)
Male:
- large low set ears, long thin face, high arched palate, macro-orchidism, hypotonia, mitral valve prolapse, LDs, autism is common
Characteristic features of Toxoplasmosis?
others?
- Cerebral calcification
- Chorioretinitis
- hydroCephalus
- anaemia, hepatosplenomegaly, cerebral palsy
Features of Wilm’s nephroblastoma?
- abdo mass, flank pain, painless haematuria, anorexia, fever
- 95% UL
- 20% have mets (commonly lung)
- usually under 5s
Wilms’ nephroblastoma associations? (4)
- Beckwith-Wiedemann syndrome
- WAGR syndrome (aniridia, GU malform, mental retardation)
- hemihypertrophy
- 1/3 ass with loss-of-function mutation in WT1 gene on chr 11
Management of Wilm’s nephroblastoma?
nephrectomy
chemo
RT if advanced
80% cure rate (good prognosis)
Histology: epithelial tubules, areas of necrosis, immature glomerular structures, stroma with spindle cells, small cell blastomatous tissues resembling the metanephric blastema
Wilms’ nephroblastoma
Classic definition of anticipation?
When unstable expansions (abnormal no of repeat trinucleotides) can enlarge leading to an EARLIER AGE OF ONSET in successive generations… often also with more severe phenotype
Genetics of DiGeorge deficiency?
- autosomal dominant
- microdeletion on chr 22
- 1ry immunodeficiency disorder caused by T-cell deficiency & dysfunction
- aka velocardiofacial syndrome
- 22q11.2
Features of DiGeorge syndrome? CATCH22
variable presentation
Cardiac abnormalities Abnormal facies Thymic hypo/aplasia Cleft palate Hypocalcaemia/hypoPTH (hypoplasia of parathyroid gland) 22 deletion
Also to rmr: at risk of viral & fungal infections; T-cell deficiency/dysfunction
Genetics of Anderson-Fabry disease
- X-linked recessive
- Alpha-galactosidase A deficiency (normally responsible for breakdown of globotriaosylceramide)
- Leads to abnormal deposits of globo… (fatty substance) that accumulate in BV walls leading to narrowing
Features of Anderon-Fabry disease? MSK heart kidney skin/eye
- limb pain/paraesthesia esp in childhood, sensory neuropathy, Raynaud’s disease
- early CVD, cardiac arrhythmias, cardiomyopathy
- nephrotic syndrome: proteinuria
- angiokeratomas, anhidrosis, cornea verticillata
Genetics of Alkaptonuria (ochronosis)
- rare autosomal recessive disorder of phenylalanine & tyrosine metabolism caused by a lack of homogentisic deoxygenate (HGD) leading to build-up of toxic homogentisic acid
- kidneys filter this acid (hence black urine), but eventually it accumulates in cartilage etc
Features of Alkaptonuria
- generally benign & often aSx however
- pigmented sclera
- black urine if left exposed to air
- intervertebral disc calcification -> back pain
- renal stones
Treatment of Alkaptonuria
- high-dose vitamin C
- dietary restriction of phenylalanine & tyrosine
Examples of trinucleotide repeat disorders (think neuro)
Fragile X Huntington's myotonic dystrophy Friedrichs ataxia spinocerebella ataxia spinobulbar muscular atrophy dentatorubral pallidoluysian atrophy
What is Ebstein’s anomaly?
Potential cause?
2 associations?
congenital heart defect characterised by low insertion of the tricuspid valve -> large atrium & small ventricle = ‘atrialisation’ of the RV
- lithium exposure in-utero
1. WPW syndrome
2. tricuspid incompetence (PSM, giant V waves)
Genetics of familial hypercholesterolaemia?
autosomal Dominant 1/500 people
gene mutation encoding LDL-receptor protein
A primary immunodeficiency disorder caused by T-cell deficiency and dysfunction?
DiGeorge syndrome
- microdeletion syndrome
- therefore at inc risk of viral & fungal infections
Autosomal dominant conditions
achondroplasia acute intermittent porphyria adult polycystic kidneys antithromb III deficiency Ehlers-Danlos Gilberts familial adenomatous polyposis hereditary haemorrhagic telangiectasia hereditary spherocytosis hereditary non-polyposis colorectal carcinoma Huntington's disease hyperlipidaemia type II hypokalaemia periodic paralysis malignant hyperthermia Marfans myotonic dystrophy neurofibromatosis Noonan syndrome osteogenesis imperfecta Peutz-Jeghers syndrome retinoblastoma Romano-ward syndrome tuberous sclerosis von Hippel-Linday sundrome von Willebrands disease
