introduction to genetic disorders, classification 26 10-2016

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Dr. Mangala G

Learning Objectives• Familiar with the different branches of genetics• Able to recollect and understand the basic concepts

in genetics like penentrance, pleiotropy etc.• Able to explain the basis of classification of genetic

disorders• Able to list the single gene disorders• Able to explain the principles of Mendelian law of

inheritance• Able to explain/discuss the biochemical/molecular

basis of single gene disorders

CytogeneticsIt deals with the study of chromosomes

and of sex chromatin Developmental genetics Genetic control of physiological

processes in the initial prenatal period of 12 weeks

• Biochemical genetics Proteins make a structural

protein/enzyme that control various metabolic processes in the body thereby influencing growth and differentiation

Mutations in DNA --- VARIANT protein synthesis --- phenotypic effect

1. Gene mutations leading to inborn errors of metabolism

2. Haemoglobinopathies3. Polymorphisms revealed by an altered

response to drugs Immunogenetics It deals with the genetic basis of the

immunological phenomenon in an organism

Cancer genetics

Population genetics

It deals with the study of genes in population.

It also tells us about distribution of genes and how genotypes are maintained or changed in population.

Pleiotropy

• Phenomenon in which a single gene mutation leads to many phenotypic effects is called pleiotropism

• Eg: Marfan’s syndrome• Single gene mutation in gene fibrillin affects

connective tissue component of skeleton, eye and CVS leading to dislocated lens, mitral valve prolapse

Genetic heterogeneity

• Phenomenon in which mutations at different genetic loci produce same result is called genetic heterogeneity

• Eg: Retinitis pigmentosa

Penentrance

• Phenotypic expression of an inherited mutant gene / percentage carriers of the gene that express the trait is called penentrance

• When some individuals inherit the mutant gene but are phenotypically normal (person may have the abnormal gene but never expressed the disease) trait is of reduced penentrance

Variable expressivity

• If a trait is seen in all individuals carrying the mutant gene but express the disease with different severity it is called variable expressivity

• Eg: neurofibromatosis

Type of mutations (based on the extent of damage)

Genome mutation: (whole chromosome) loss or gain of whole chromosome giving rise to

monosomy or trisomy

Chromosome mutation: (visible chromosome change)Rearrangement of genetic material giving rise to visible

changes in the chromosome– Gene mutation: (may, and often, result in a single

base error)

GENETIC DISORDERS

Single gene mutations, following classical Mendelian inheritance patterns

Multifactorial inheritance Chromosomal disorders Structural /numerical abnormalities in

autosomes and sex chromosomes

Multifactorial inheritance

Diseases involved by both genetics as well as environmental influences

Caused by interaction between multiple variant forms of genes and environmental factors

No single susceptible gene is individually sufficient for inducing the disease

Eg: Cleft lip or palate Congenital heart disease, Coronary heart disease Hypertension, Type II DM

SINGLE-GENE DISORDERS These disorders are the result of mutation of a

single gene of large effect

Mutation refers to PERMANENT change in DNA muatations that affect germ cells - transmitted to progeny - give rise to inherited disorders mutations in somatic

cells - not transmitted to progeny - give rise to cancers and congenital malformations

GENE MUTATIONS• Point mutation• Substitution of a single nucleotide base by

a different base• Val ----- Glutamic acid• Frame shift mutation • Insertion / deletion of one or two base

pairs in the DNA sequence Eg: Cystic fibrosis of pancreas

Tri-nucleotide REPEATSAmplification of a sequence of three

nucleotidese.g., CGG repeats many times in fragile X

syndromeMutations involving single genes typically

follow one of three patterns of inheritance: Autosomal dominant Autosomal recessive and Sex-linked recessive ( X- chromosome )

AUTOSOMAL DOMINANT

• Disease is in HETEROZYGOTES• NEITHER parent may have the disease (NEW mut.)• REDUCED PENETRANCE (env?, other genes?)• VARIABLE EXPRESSIVITY (env?, other genes?)• May have a DELAYED ONSET• Usually result in a REDUCED PRODUCTION or

INACTIVE protein

Autosomal Dominant• Manifested in the heterozygous state• Atleast one parent of an index case is usually

affected• Both males and females affected, both can

transmit the disease• New mutations can occur – neither siblings are

affected nor they have affected parents• Incomplete penentrance• Variable expressivity• Delayed onset

AUTOSOMAL DOMINANT PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS NOT SKIPPED

Examples

Huntington disease Neurofibromatosis Polycystic kidney Hereditary spherocytosis Von willebrand disease Marfan syndrome EHLERS-DANLOS syndromes(some) Familial hypercholesterolemia

• Clinical features can be modified by variations in penentrance and expressivity

• Eg: Neurofibromatosis type 1 brownish spots on the skin to multiple skin

tumors and skeletal deformities

Autosomal recessive disorders

• Most common type of Mendelian disorder• Parents may not show the disease, but siblings

may• Siblings have one chance in four of having

trait• Expression of defect more uniform than in AD• Complete penentrance is common• Early onset in life

AUTOSOMAL RECESSIVE PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS SKIPPED

Examples PhenylKetonUria Galactosemia Lysosomal storage diseases Wilson disease Hemochromatosis Glycogen storage diseases Sickle cell anemia Thalassemias EHLERS-DANLOS (some) Alkaptonuria

Heredity in hemophilia

Normal women Affected male

Gametes

Children

Parents

Trait-carrying Normal Trait-carrying NormalGirl boy girl boy

Heredity in hemophilia

Gametes

Children

Parents

Normal Normal Trait-carrying Affected girl boy girl boy

Examples

Duchenne muscular dystrophy Hemophilia , A and B G6pd deficiency Wiskott-aldrich syndrome Diabetes insipidus Lesch-nyhan syndrome Fragile-x syndrome

Biochemical and molecular basis of Single-gene (Mendelian) disorders

1. Enzyme defects and their consequences

2. defects in membrane receptors and transport systems

3. alteration in the structure, function or quantity of non-enzyme proteins

4. Mutations involving unusual reaction to drugs

Enzyme defects and their consequences• Mutations result in the synthesis of an enzyme

with reduced activity / reduced amount of normal enzyme

• Metabolic block• A) accumalation of substrate eg: accumalation of substrates in the lysosomes

due to deficiency of degradative enzymes – lysosomal storage diseases

• an enzyme defect leading to decreased amount of end product

• Eg: albinism def. of tyrosinase leads to reduced synthesis

of melanin from tyrosine

Defects in the receptors and transport systems

• Eg: reduced synthesis/function of LDL receptor leads to defective transport of LDL into cells --- excessive cholesterol synthesis --- familial hypercholesterolemia

• Cystic fibrosis --- transport system for chloride ions is defective in sweat glands, lungs and pancreas

Alteration in structure, function / quantity of non-enzyme proteins

• Thalassemia – reduced amount of alpha/beta chains

• Defective structural proteins – collagen, spectrin / dystrophin

• Osteogenesis imperfecta, hereditory spherocytosis and muscular dystrophies

Genetically determined adverse reaction to drugs

• Eg: G6PD Hemolytic anemia on taking antimalarial drug

Primaquine

MCQ’s1. Albinism results from deficiency of A) CatalaseB) TyrosinaseC) Xanthine oxidaseD) Pyruvate kinase2. Most striking example of disease due to

point mutation E) Sickle cell anemiaF) Down’s syndrome

3. In human beings, multiple genes are involved in the inheritance of

A) Sickle cell anemiaB) HaemophiliaC) PhenylketonuriaD) Skin colour4. G-6-PD is associated with the hemolysis ofA) LymphocytesB) NeutrophilsC) RBC’sD) Platelets