Medical Genetics Flashcards
Familial Adenomatous Polyposis (FAP)
Mutation in PAC gene
Predisposition to developing hundreds or thousands of bowel polyps
If left untreated, cancer is inevitable
Polyps develop during teenage years
Cancer in early 20s common
Prophylactic colectomy is standard treatment
Hereditary breast and ovarian cancer
BRCA1/2
BRAC1 chromosome 17q, BRAC2 chromosome 13q
Function as DNA repair genes
Risk: several relatives with cancers, age of diagnosis, bilateral breast cancer, breast and ovarian cancer in same individual, male breast cancer, inheritance pattern (dominant?), Jewish ancestry
Hereditary non-Polyposis colorectal cancer (HNPCC) or Lynch Syndrome
Mutations in MLH1, MSH2, MSH6
Autosomal dominant
Inherited mutations that impair DNA mismatch repair
Suspect: several relatives with bowel cancer under 60, any relative with bowel cancer under 45, double bowel cancer, presence of other cancers in family history (endometrial, ovary, stomach, small bowel
Li-Fraumeni syndrome
Mutations in P53
Cell cycle control gene –> tumour suppressor
Autosomal dominant
Extremely rare
Penetrance about 90% - higher for women who don’t have mastectomies
Causes variety of cancers - sarcoma, breast, leukaemia, adrenal cortical, brain, colon
Multiple endocrine neoplasia
Mutation in MEN1, MEN2, autosomal dominant
MEN1: pituitary (acromegaly, abnormal lactation), pancreas (diabetes), parathyroid (calcium disturbance, kidney stones)
MEN2: medullary thyroid cancer, phaeochromocytoma, parathyroid tumours
Achondroplasia
Autosomal dominant
Dwarfism, prominent forehead, depressed nasal bridge, restricted foramen magnum, waddling gait
FGFR3 in growth plate, mutation causes premature differentiation of chondrocytes
Liveborn homozygotes are extremely short limbed, asphyxiating dysphasia causing neonatal death, hence chance of offspring of two dwarf parents is 2/3
Huntington’s disease
Autosomal dominant
Dementia and abnormal movements starting age ~40
Death within 10-15 years
Huntingtin gene normally has highly polymorphic CAG repeats, abnormally expanded in slippage of DNA polymerase during spermatogenesis, leads to ab rims, aggregation of Huntington in brain
Marfan syndrome
Autosomal dominant
Tall, long fingers, fibrillin defect so aortic instability, sudden death, scoliosis, prolapse of mitral valve, aortic aneurysm
Excessive elasticity of fibrillin-1. Mutant protein binds to and disables normal fibrillin
Tay-Sachs disease
Autosomal recessive
Common in Jewish population.
Neuro deterioration and death starting age 4-5, leading to loss of sight, hearing, and to spasticity, rigidity and death from respiratory infection
Defective a-subunit of hexosaminidase-A allows accumulation of GM2 ganglioside
cystic fibrosis
Autosomal recessive
Common in Caucasians
Lung and pancreas problems
Chronic obstructive airway disease due to thick mucus, accompanied by bacterial infection and destruction of lung tissue. Congenital absense of the vas deferens in almost all males
CFTR defect, forms cAMP regulated chloride channels in epithelial cells. Synthesis of protein is either blocked or reduced leading to salt imbalance and water depletion
Sickle cell anaemia
Autosomal recessive
Sickling of red cells, poor oxygen carriage, painful crises, stroke
Point mutation substitution on beta haemoglobin, glutamine to valine residue at position six, abnormal haemoglobin tends to aggregate
Albinism
Mostly autosomal recessive
No pigment in hair and eyes, photophobia, involuntary eye movements nystagmus
Susceptibility to skin cancers
Defect in tyrosinase which normally converts tyrosinase though DOPA into DOPA quinine, precursor of melanin
Haemophilia
X-linked recessive
Lack of factor VIII, disrupt conversion of prothrombin to thrombin through inversions, major deletions and non-sense mutations
Poor clotting, joint pains, visible bruising, haemorrhage
Colour-blindness
X-linked recessive
Red-green Colour blindness
On each X chromsome is a gene for red-sensitive ops in immediately adjacent to one or serveral green operon genes. Sequences are very similar promoting a tendency for crossover errors, creating hybrid genes
Duchesse muscular dystrophy
X-linked recessive
Progressive loss of muscle power
Respiratory failure and death by 20s
Rett syndrome
X-linked dominant
Mental retardation in girls, autistic, epilepsy, breathing irregularities, stereotyped hand movements (wringing)
Regression after age 1-2
Mutation in MECP2, protein product fails to regulate transcription of genes concerned with brain development
Hypophosphataemic rickets
X-linked dominant
Functional calcium deficiency, kidneys have impaired ability to resorb phosphate resulting in abnormal ossification
Joint swelling, bony deformity
Myoclonic epilepsy with ragged red fibres (MERRF)
Mitochondrial
Mental retardation, progressive myoclonic epilepsy, slowly progressing dementia and topic atrophy
Characteristic appearance of muscle on biopsy
Point mutation in gene for tRNA lysine
Mitochondrial encephalopathy lactic acidosis, stroke (MELAS)
Mitochondrial
Mental retardation
Metabolic problems and strokes, vomiting, headache or visual disturbance, type 2 diabetes
80% have two substitutions in a leucine tRNA
