Genetically Inherited conditions Flashcards
Classification of genetic disorders
Multifactorial –> single gene –> chromosomal –> mitochondrial –> Somatic mutation
Genetic factors for different classification (multifactorial, single gene & chromosomal)
Multifactorial diseases (common) - variants in genes causing alteration in function
Single gene disorders (1% live-born)
- single gene mutation
Chromosome disorders (0.6% live-born) - chromosomal imbalance = alteration in gene dosage
Impact of genetic disorders
Childhood:
- 50% deafness/blindness/severe MR
- 40-50% of deaths
Adult life:
- 5% disorders/diseases
- 10% common cancers
Diagnosing Down’s syndrome
Features on face:
- round, protruding tongue, upslanting palpetral fissures, epicanthic folds
Diagnosis from ultrasound (21+ weeks):
- short femurs, nuchal translucency, echogenic bowel, sandal gap in toes
Causes of Down’s syndrome
3 patterns of chromosomes can cause Down’s:
1) 95% of people have Trisomy 21 (3 chromosomes at position 21 of karyotype)
2) 4% have an extra copy of chromosome 21 due to Robertsonian translocation (chromosome attaches to another chromosome)
3) 1% have mosaicism where a mix of normal and Trisomy 21 cell lines are present (occuring postzygotically). Milder feature due to normal cell presence
Trisomy 13 (Patau syndrome)
1: 5000 births: fatal prognosis & death within weeks
- incomplete lobulation of brain and congenital heart disease
Chromosomal non-disjunction occurs
Chromosomal non-disjunction
Crossing over doesn’t occur on metaphase plate & a chromosome goes the wrong way at anaphase
- produces nullisomic gametes (missing chromosomes) and disomic gametes (doubled chromosome levels)
Other chromosomal abnormalities
- gain/loss of chromosomes has serious, often lethal consequences (especially autosomal anomalies)
» e.g. multiple congenital anomalies/mental retardation (MCA/MR) syndromes - autosomal monosomies = catastrophic
- fewer serious effects from sex chromosome abnormalities
Microdeletion causes and examples
Chromosomal regions are lost and are identified using specific molecular cytogenic techniques
e. g. DiGeorge syndrome: 22q11.2 microdeletion
- small mouth, prominent nose, congenital heart defects
e. g. Williams syndrome: 7q11.23
- bright eyes, stellate irides, wide mouth, upturned nose, long philtrum, flattened nasal bridge, heart defects, very sociable
e. g. Prader-Willi syndrome: 15q13
- hyperphage (unable to control appetite), psychiatric effects
e. g. Cat eye syndrome: inverted duplication of chromosome 22
- incomplete circle of iris muscle
Single gene disorder causes
Can be dominant, recessive or X-linked:
- autosomal dominant: Huntington’s, neurofibromatosis
- autosomal recessive: Cystic fibrosis, spinal muscular atrophy
- X-linked: Fragile-X mental retardation syndrome, Duchenne Muscular dystrophe
High risk to relatives, affecting structural proteins, enzymes, receptors and transcription factors
Single gene disorder examples
Sickle Cell Anaemia
- Point mutation A –> T changes Glutamic acid to Valine
Huntington disease
- involuntary head/face movements, loss of brain tissue
Familial Hypercholesterolemia
- cholesterol deposition in heterozygotes: tendon xanthomata & corneal arcus. Cardiovascular disease
Autosomal recessive Senorineural deafness
- Single mutation in connexin 26: Val –> STOP
Duchenne Muscular Dystrophe
- disorganisation of muscle tissue without dystrophin
Mitochondrial inheritance & disease
e. g. Leber’s hereditary optic neuropathy
- optic atrophy and hyperemia of optic disc
- reduction in vision
Multifactorial inheritance
Inheritance controlled by many genes all affecting just one organ (small additive environmental effect)
- lots of small-effect genetic influences
Learnt disease mechanisms from Mendelian studies
- e.g. understanding Type 1 diabetes from Type 2 (linked mutated genes for glucokinase TFs to development/functioning of pancreatic B cells
