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

http://jnnp.bmj.com/content/73/suppl_2/ii5/F1.large.jpg

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