Genetics Flashcards
Inheritance of Leders Hereditary Optic Neuropathy
Mitochondrial with Heteroplasmy so variable expression and arises later in life
(Individuals do not experience vision difficulties until adulthood because only some mitochondria have mutant copies of gene
Causes bilateral, painless subacute loss of central vision during young adult life)
Gonadal/Germiline mosaicism
where an individuals germline cells develop mutation during embryonic growth but the somatic cells do not this results in the individuals offspring being affected, but not themselves.
Parent will not have mutated somatic cells on testing, but offspring will.
Linkage Disequilibrium
Linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. There is associations in populations of alleles more than what would be expected if they were unlinked.
Disorders with Trinucleotide repeats
Huntingtons - CAG repeats
Frederich Ataxia - GAA repeats
Myotonic dystrophy - Autosomal dominant with CTG repeats
Fragile X - X linked with CGG repeats
Mutations in variants of Muscular Dystrophy
All X-linked recessive
- Duchenne MD - frame-shift mutation (worst)
- Beckers MD - In-frame mutation
- MD Cardiomyopathy - Promoter region mutation (best)
Examples of diseases with Frame-shift mutations
- CCR5 receptor in HIV
- Duchennes MD
- Tay-Sachs disease (usually causes death as toddler_
What pattern in a pedigree makes autosomal dominant likely?
Father to Son transmission
Types of point mutations/single nucleotide variants
Frame-shift due to insertion or deletion that are not multiples of 3
Nonsense results in unwanted stop codon
Missence results in single different amino acid
Splice mutations occur at site of intron and exon splicing which can cause loss of exon or inclusion of intron altering the protein code
Imprinting disorders
Has phenotypic effect if Pt has inherited 2 copies of genes from one parent and none from other, then the copies are imprinted
- Prader Willi Syndrome
- Angelmans syndrome
- Beckwith Weidman Syndrome
- Russel Silver Syndrome
- Transient neonatal hypoglycaemia
- matUPD14
- patUPD14
- Pseudohypoparathyroidism
X-linked dominant disorder
Rett syndrome - primary females affected, growth and IQ disabilities
Autosomal dominant disorders
Cardiac congenital disorder except Fabrys;
- Brugada
- Long QT syndrome
- Arrythmogenic RV cardiomyopathy
- HCM
- Marfans
- Loey Dietz
- Myotonic dystrophy
- Familial Adenomatous Polyposis
- Huntingtons disease
- Neurofibromatosis Type 1
- Familial Hypercholestraemia
Trinucleotide disorders
- Huntingtons, autosomal dominant (> 40 CAG repeats)
- Fredreichs Ataxia, autosomal recessive (CGG repeats)
- Myotonic Dystrophy, autosomal dominant (CTG repeats)
- Fragile X , X-linked (mixed recessive and dominant - CGG repeats)
- Spinocerebellar Ataxia, autosomal dominant
Mitochondrial disorders
Heterozomy - Leber Optic atrophy with blindness in older age
Homozomy - MELAS, Myoclonic epilepsy with ragged red fibres
Uniparental Disomy
2 x chromosomes from ONE parent. Only causes an issue if imprinted chromosomes
i.e. Prader Willi, Angelmans
Linkage Disequilibrium
A correlation between nearby alleles at neighboring polymorphs are associated within a population more often than if they were unlinked.
Alpha thalassemia
4 genes on Chromosome 16
Autosomal recessive
AAAA - normal
aAAA - silent
aaAA - minor
aaaA - HbH (4 x beta tetramer)
aaaa - hydros fetalis w Barts Hb (gamma tetramer, due to insufficient switching from metal Hb kappa-gamma to alpha-gamma)
Beta thalassemia
2 genes on Chromosome 11
Autosomal recessive
AA - normal
aA - minor/intermediate
aa - Major (forms HbA2 - 2 x alpha, 2 x delta chains)
Different Hb’s in Thalassemia
HbA - normal - 2 x alpha, 2 x beta
HbF - normal fetal - 2 x alpha, 2 x gamma
HbA2 - 2 x alpha, 2 x delta
HbH - 4 x beta
Barts Hb - 4 x gamma in hydrops fetalis
Congenital Heart Disease - Turner syndrome
XO
Bicuspid aortic valve
Less commonly coarctation of aorta
Congenital Heart Disease - Downs Syndrome
Trisomy 21
Tetralogy of Fallot
Inheritance Prader Willi
Ch 15 q11 deletion or imprinting in context of Uniparental Disomy
Inheritance Angelmans
Ch 15 q12 deletion or imprinting in context of Uniparental Disomy
Choroid villous sampling Vs. amniocentesis
Choroid;
< 11 weeks with 2% risk
Amnio;
< 16 weeks with 1% risk
Pateu Syndrome
Trisomy 13 - characteristic fist clench (along with Trisomy 18)
Edwards Syndrome
Trisomy 18 - characteristic fist clench (along with Trisomy 13)
Mainfestations DiGeorges Syndrome
CATCH 22
- Cardiac abnormalities - TOF/VSD/Truncus arteriosis
- Abnormal facies
- Thymic hypoplasia
- Cleft palate
- HypoCa, HypoPTH
- 22q11.2 deletion
Huntington Disease Inheritance
Autosomal Dominant
Trinucleotide repeats CAG > 40
Juvenile HD CAG > 60
Worse trinucleotide instability if inherited from Father due to spermatogenesis CAG instability
Spinocerebellar ataxia
Autosomal dominant
SCA gene
Repeat expansion
Ataxia with spinal and cerebellar degeneration
Onset in 30’s
Myotonic Dystrophy
Autosomal dominant
CTG repeats
DMPK gene (dystrophin myotonica protein kinase)
Worse with maternal inheritance
Percussion myotonia
Weakness
Cataracts
Cardiac conduction abnormalities
Testicular Atrophy
CK rise in Duchennes/Beckers MD
DMD - CK > 10 x ULN
Beckers - CK > 5 x ULN
Marfans inheritance
Autosomal dominant
FBN1 gene
(fibrin variants)
Diagnosis of Marfans
FBN1 gene
Aortopathy/aortic score > 2
Systemic score > 7
Lens dislocation
FHx
Loey Deitz Syndrome
Aortopathy without lens dislocation - can be more severe than Marfans
Due to TGF gene mutations
Indications for surgical intervention AAA
Idiopathic/metabolic > 55mm
Marfans > 50mm
Loey Dietz > 42mm
Or increasing > 0.5cm/year
Noonans Syndrome
PTPN11 gene mutation
Rasopathy
Autosomal dominant
Pulmonary stenosis
HCM
P’s
- PTPN11
- Pulmonary Stenosis
- rasoPathy
- Predisposed malignancy
Inheritance Neurofibromatosis type 1
Autosomal dominant
NF1 gene
Increased risk malignancy including optic nerve glioma in children
Cancers associated with Neurofibromatosis Type 1
Optic glioma in children
Breast Cancer
Pheochromocytoma
Peripheral nerve sheet tumour
Tuberous Sclerosis
Autosomal dominant
TSC1 (hamartin) and TSC2 (tuberin) gene mutation causing tumours and seizures
Associated with Lymphangioleiomyomatosis of lungs (+++ cysts throughout lungs)
Pathogenesis of genetic cardiomyopathies
HCM - Sacromere disease
ARVC - Desmosomes with fibrofatty infiltration
Fabrys - Lyosomes deposition
