Download - genetics ppt 01
HUMAN GENETICS
Dr. D.A.R.K. Dayarathna
MD (medicine –col),
MSc (medical genetics –Ncl - UK)
Genetics
• Human genetics- scientific study of human variation and Heredity
• Medical genetics - study of the hereditary nature of human disease
• Clinical genetics- Care, diagnosis and counseling of patients with congenital malformations or genetic diseases
Causes of diseases
• Accidents
• Infections
• Genetic diseases
• Complex traits
Genetic diseases
• Inherited diseases
• Diseases due to mutations in somatic cells- cancer
Inherited diseases
• Due to genetic mutations- nuclear, Mitochondrial
• Chromosomal abnormalities
• Complex traits, multifactorial disorders
Mutations• Deletions- ranging from 1 bp to mega base• Insertions- including duplications• Single base substitution-• Missense mutations- replace one amino
acid with another in the gene product• Nonsense mutations replace one amino
acid codon with a stop codon• Splice site mutations create or destroy
signals for exon/intron splicing• Frame shifts can be produced by
deletions, insertions or splice mutations
Mutation- functional change
• Loss of function mutations• Gain of function mutations
Loss of function
• Autosomal recessive disorders
Autosomal dominant
• Dominant negative• Haplo insufficiency
Dominant negative mutation
Karyotype
Gene structure and protein synthesis
GENE expression
Down syndrome
Down syndrome
• Common cause for mental retardation
• Most are due to trisomy 21,nodisjunction
• Elderly mothers are more suseptible
• 2-3% due to translocatin of 21to14
• Screening – triple test
- alpha feto protien
-oestriol
- chorionic
gonadotopihic hormone
- ultra sound scan
-amniocentesis
Turner syndrome
Klinefelter syndrome
Fragile X syndrome
Fragile X syndrome• Inherited cause of
intellectual disability
• Large protruding ears,large testiclesle
• Due to mutation of the fragile X mentel retardation 1 ( FMRI)
• X linked dominent condition with variable expressivity
Autosomal dominant inheritance
• Males and females are equally affected• Transmission between all sexes are
observed . Male to male, female to male• Symptoms usually appear later in life• Pleiotrophy- single gene disorder produce
multiple phenotypic effect• Variable expressivity of gene
• Reduced or incomplete penetrance, the
penetrance is expressed as a percentage
Autosomal dominant ctd
• Codominance- when both traits are expressed fully in heterozygous state. Ex-AB blood group
• Intermediate inheritance• Ex- sickle cell trait
Pedigree symbols
Achondroplasia
•Common genetic cause of dwarfism
•Mutation in the fibroblast growth factor receptor
3(FGFR3)
•Cause abnormality of cartilage formation
•Can be detected before birth by prenatal
ultrasound
Autosomal dominant polycystic kidney disease
•Inherited systemic disease
• 1 in 400 to 1 in 1000
•Mutation in PKD1 and PKD 2 gene
•Cyst in liver, pancreas, cerebral aneurysm, mitral
valve prolapse.
•Imaging and molecular studies
Neurofibramatosis•Skin fibromas
•Neuro fibromas
•Capu lau spot
•Variable clinical manifestation
Hereditary spherocytosis
Hypertropic obstructive cardiomyopathy
• Presentation
Sudden death
Chest pain on excretion
palpitation
Mafan syndrome
Osteogenesis imperfecta
Familial hypercholesterolemia
Brugada Syndrome
• More in asia
• Cause of sudden death in young
• Can present with atypical chest pain and recurrent palpitation
• Mutation in sodium ion channels
• Cause of death is VF
• Implantable cardioverter defibrillator
Autosomal recessive inheritance
• Presentation - in early age, usually with severe symptoms
• Affect either sex
• Affected people are usually born to unaffected parents
• Parents are usually asymptomatic carriers
• Increase incidence of parental consanguinity
• After the birth of an effected child, each subsequent child has a 25% of being Affected
Autosomal recessecive pedigree
Thalasaemia
Albinism
White Tiger
X linked recessive inheritance
• Affect mainly males• Affected males are usually born to un
affected parents• Mother is normally an asymptomatic
carrier• There is no male to male transmission in
the pedigree
Color blindness(X-linked)
Duchenne muscular dystrophy• Common inherited
muscular dystrophy
• Mutation in dystrophin gene
• Symptoms before age of 05
• Progressive muscle weakness
• Pseudo hypertrophy of calf muscles
• Cardiac involvement
Lyon hypothesis
• Random inactivation of one X chromosome in early foetal development
X linked dominant inheritance
• Affect either sex but more female then males
• Female are often more mildly and more variably then males
• No male to male transmission
Mitochondrial inheritance
• Matrineal inheritance• Variable clinical manifestation due to
heteroplasmy
Mitochondrial inheritance ctd
Mitochondrial disease
• Ragged Red Fibers" - clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stain
E/M view of diseased mitochondria
Mitochondrial myopathies
• Kern sayare syndrome
• Chronic progressive external opthalmoplegia
Complex traits
Diabetes mellitus, Hypertension, mental disorders etc
Complex traits ctd
• Gene and environment interaction• Population studies• Family studies• Twin studies