This document provides an overview of genetics and genetic disorders. It discusses various branches of genetics including cytogenetics, developmental genetics, biochemical genetics, immunogenetics, cancer genetics, and population genetics. It describes key genetics concepts such as pleiotropy, genetic heterogeneity, penetrance, and variable expressivity. It also discusses different types of genetic mutations and inheritance patterns including autosomal dominant, autosomal recessive, and sex-linked recessive. Finally, it provides examples of single-gene disorders and explains the biochemical and molecular basis of some common genetic disorders.

2. Dr. Mangala G

3. 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

4. Cytogenetics
It 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

5. • 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

6. 1. Gene mutations leading to inborn errors
of metabolism
2. Haemoglobinopathies
3. Polymorphisms revealed by an altered
response to drugs
Immunogenetics
It deals with the genetic basis of the
immunological phenomenon in an
organism
Cancer genetics

7. 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.

8. 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

9. Genetic heterogeneity
• Phenomenon in which mutations at different
genetic loci produce same result is called
genetic heterogeneity
• Eg: Retinitis pigmentosa

10. 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

11. 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

12. 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)

13. GENETIC DISORDERS
 Single gene mutations, following
classical Mendelian inheritance patterns
 Multifactorial inheritance
 Chromosomal disorders
Structural /numerical abnormalities in
autosomes and sex chromosomes

14. 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

15. 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

16. 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

17. Tri-nucleotide REPEATS
Amplification of a sequence of three
nucleotides
e.g., CGG repeats many times in fragile X
syndrome
Mutations involving single genes typically
follow one of three patterns of inheritance:
 Autosomal dominant
 Autosomal recessive and
 Sex-linked recessive ( X- chromosome )

18. 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

19. 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

20. AUTOSOMAL DOMINANT PEDIGREE
1) BOTH SEXES INVOLVED
2) GENERATIONS NOT SKIPPED

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

22. • 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

23. 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

24. AUTOSOMAL RECESSIVE PEDIGREE
1) BOTH SEXES
INVOLVED
2) GENERATIONS
SKIPPED

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

26. Heredity in hemophilia
Normal women Affected male
Gametes
Children
Parents
Trait-carrying Normal Trait-carrying Normal
Girl boy girl boy

27. Heredity in hemophilia
Gametes
Children
Parents
Normal Normal Trait-carrying Affected
girl boy girl boy

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

29. 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

30. 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

31. • an enzyme defect leading to decreased
amount of end product
• Eg: albinism
def. of tyrosinase leads to reduced synthesis
of melanin from tyrosine

32. 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

33. 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

34. Genetically determined adverse
reaction to drugs
• Eg: G6PD
Hemolytic anemia on taking antimalarial drug
Primaquine

35. MCQ’s
1. Albinism results from deficiency of
A) Catalase
B) Tyrosinase
C) Xanthine oxidase
D) Pyruvate kinase
2. Most striking example of disease due to
point mutation
A) Sickle cell anemia
B) Down’s syndrome

36. 3. In human beings, multiple genes are involved
in the inheritance of
A) Sickle cell anemia
B) Haemophilia
C) Phenylketonuria
D) Skin colour
4. G-6-PD is associated with the hemolysis of
A) Lymphocytes
B) Neutrophils
C) RBC’s
D) Platelets