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
Prader-Willi syndrome
Uniparental disomy: mutation (visible deletion and microscopic deletion at 15q11-12) in male PWS gene
Floppy babies who fail to thrive initially then extreme obesity and slight mental retardation
Angelman syndrome
Uniparental disomy, mutation in female Angelman gene
Severe mental retardation, ‘happy puppet’, epilepsy, uncoordinated movements and compulsive laughter
Fragile X syndrome
X-linked recessive (expansion)
Mental retardation in boys, large head, nose, ears, testicles (post-pubertally)
Premature ovarian failure in female carriers
FRAX-A full mutation leads to methylation of the promoter and lack of expression of the gene product
CADASIL
Autosomal dominant
Early onset dementia
Thanatophoric Dwarfism
New mutations (autosomal dominant) Lethal form of dwarfism with skull abnormalities
Turner syndrome
45X
Female, short, no puberty, webbed neck, shield chest, wide carrying angle, normal intelligence
Klinefelters syndrome
47XXY
Male, tall, small gonads, breasts, infertile, slight mental retardation
Triple X
47XXX
Female, tall, mild mental retardation
Down’s syndrome
47XX (or XY) +21 (or Robertsonian translocation)
Characteristic face, upslanting eyes, apparently lagged tongue, single palmar crease, wide sandal gap, heart defects, mental retardation, Alzheimer’s later
Patau syndrome
47XX (or XY) +13
Severe mental retardation, clefting, sometimes Cyclopia, unlikely to survive 1st year
Edwards syndrome
47XX (or XY) +18
Severe mental retardation, heart defects, overlapping fingers, rocker bottom feet, unlikely to survive 1st year
DiGeorge syndrome
22q11 deletion
Mild mental retardation, cleft palate, immunodeficiency, schizophrenia in adults
WAGR
11p13 deletion
Wilms tumour-aniridia-genital abnormalities
Retardation
Williams syndrome
7q11 deletion
Mild mental retardation, cocktail party chatter, hypercalcaemia, heart defects
Myotonic dystrophy 1
Autosomal dominant
Tonic muscle spasm with prolonged relaxation, cardiac defects, disturbed gastro-intestinal peristalsis,meal sphincters
Expanded CTG trinucleotide repeat in DMPK gene (a protein kinase)
Cleft palate
Failure of fusion of frontal and maxillary processes and includes chromosomal, teratogenic, monogenic and mutlifactorial forms.
Congenital dislocation of the hip
Most commonly found in girls
Multifarious, positively associated with breech birth and neuromuscular disorder, and when babies swaddled
Congenital heart defects
Ventricular septum defect, atrial septal defect, patent ductus arteriosus, pulmonary stenosis, coarctation (constriction) of the aorta, aortic stenosis (constriction of the aortic valve)
Tetralogy of Fallot
Spina Bifida
Posterior neural tube defect can lead to lumbosacral myelocele or meningomyelocele (protruding spinal cord exposed, or covered by meninges)
Pyloric stenosis
Hypertrophy and hyperplasia of the pyloric sphincter lead to projectile vomiting, constipation and dehydration in early infancy
Club foot (talipes)
Feels are plantar-flexed and inverted
Familial hypercholesterolaemia
Plasma cholesterol twice as high –> distinctive depositors in tendons and skin
Coronary artery disease, atherosclerosis, MCI in under 60 year olds
Defective LDLRs which can’t internalise LDLs
Congenital deafness
Autosomal recessive
Several forms that mimic at gross phenotypic level due to locus heterogeneity, hence two deaf people can have offspring with normal hearing
Phenylketonuria
Autosomal recessive
Inability to metabolise Phe, mental retardation if no diet
Convulsions, fair-haired, blue eyes
Deficiency in phenylalanine hydroxylase for turning phenylalanine into tyrosine
Spinal muscular atrophy
Autosomal recessive
Type 1 - werdnig-Hoffmann disease, most severe and most common. Severe hypotonia and lack of spontaneous movement, poor swallowing and respiratory function, death before 3
Type 2 - muscle weakness and hypotonia, no independent locomotion
Type 3 - relatively mild, slowly progressive muscle weakness
Due to degeneration of anterior horn cells due to inverted duplication on chromosome 5
Becker muscular dystrophy
X-linked
Red used quantity or abbreviated form of dystrophin
Rarer than duchenne
G6PD deficiency
X-linked recessive
Androgen insensitivity syndrome
Allows development of female external genitalia in XY individuals due to lack of recpetor for dihydrotestosterone
Lack menstrual periods, inguinak hernia containing testis (can develop malignant cancer)
47, XYY syndrome
47 XYY
Male, aggressive, criminal tendencies
