Genetic Inheritence

and

Chromosomal disorder

Guide-

Dr.H.P.Singh

Dr.Priyank Patel

WHAT IS

GENETICS?????The branch of biology that deals with

heredity, especially the mechanisms of

hereditary transmission and the

variation of inherited

characteristics among

similar or related

organisms

Terminology:

Gene.

Alleles- Dominant.

- Recessive.

Nucleotides.

Codon.

Genetic Code.

GENE

Biological unit of heredity.

Gene hold the information to build and

maintain their cells and pass genetic traits to

offsprings

In cells, a gene is portion of

DNA

Gene (DNA)

RNA formation

Protein formation

Cell structure Cell enzymes

cell function

ALLELS

Is one member of a pair or series of

different forms of a gene.

Homozygous-an organism in which 2

copies of genes are identical i.e. have same

alleles

Heterozygous-an organism which has

different alleles of the gene

Chromosomes:

Chromatin: DNA, RNA &

proteins that make up

chromosme

Chromatids: one of the two

identical parts of the

chromosome.

Centromere: the point where

two chromatids attach

46 chromosomes. 22 pairs

Autosomes and 1 pair Sex

chromosomes.

NUCLEOTIDE: group of molecules that when linked

together, form the building blocks of DNA and RNA;

composed of phosphate group, the

bases:adenosine,cytosine,guanine and thymine and a pentose

sugar.In case of RNA,thymine base is replaced by uracil.

CODON: series of three adjacent bases in one polynucleotide chain of a DNA or RNA molecule which codes for a specific amino acid.

GENETIC CODE: the sequence of nucleotides in a DNA or RNA molecule that determines the amino acid sequence in the synthesis of proteins.

Congential Disease.

Diseases which are present at birth.

Hereditary/Familial Disease.

Diseases which are derived from one’s

parents and trasmitted in the gametes through the

generations.

Not all congenital diseases are genetic(

congenital Syphilis) and not all genetic

diseases are congenital (Huntington disease).

Types ofMutation

Mutation

it is defined as a permanent changes in the

DNA.

Mutation that affect germ cell are

transmitted to the progeny and can give rise

to inherited disease.

• Point Mutation:

• Substitution of a

single nucleotide base

by a different base.

Missense

Mutations.

NonsenseMutations.

• FrameshiftMutations:

Insertion or deletion of one or two base pairs alters the reading frame of the DNA strand.

Classification Of Genetic

Diseases: Single Gene Defects/Mendelian Disorders.

Disorders with Multifactorial or Polygenic inheritance.

Cytogenetic Disorders.

Disorders showing atypical patterns of inheritance.

Mendelian Disorder

All mendelian disorder are the

result of mutation in single

genes that have large effecs.

Patterns Of Inheritance:

Autosomal Dominant.

Autosomal Recessive.

X-Linked Recessive.

X-Linked Dominant

Autosomal

Dominant

Disorder.

•Manifested in heterozygous states

•At least one parent of index case is usually

affected

•Both males and females are affected.

•Clinical feature can be modified by variation in

penetrance and expressivity. Some individual

inherit the mutant gene but are phenotpically

normal. This is reffered to as “incomplete

penetrance”.

•In many condition the age of onset is delayed.

Inheritance Pattern:

• Typical pattern is a heterozygous affectedparent with a homozygous unaffected parent.

• Every child has one chance in two of having the disease

• Both sexes are affected equally..

Autosomal Dominant Disorders

Nervous Huntington disease

Neurofibromatosis

Myotonic dystrophy

Tuerous Sclerosis

Urinary Polycystic Kidney disease

Gastrointestinal Familial polyosis coli

Hematopoietic Hereditary spherocytosis

Skeletal Marfan syndrome

Osteogenesis imperfecta

Achondroplasia

Metabolic Familial hypercholesterolmia

Acute intermittent

porphyria

Autosomal

Recessive

Disorder

•Largest category of Mendelian disorder

•Usually does not affect the parent of the affected

individual, but sibling may show the disease.

•Complete penetrance is common.

• Onset is frequently early in life.

•Usually affect enzymatic proteins.

Pattern Of Inheritance:

Typical pattern is two heterozygous unaffected(carrier) parent.

The triat does not usually affect the parent, but siblings may show the disease

Siblings have one chance in four of being affected

Both sexes affected equally.

Autosomal Recessive

Disorder Metabolic Cystic fibrosis

Phenylketonuria

Galactosemia

Homocystinuria

Glycogen storage dise

Haematopoietic Sickle cell anaemia

Endocrine Congenital Adrenal

hyperplasia

Skeletal Alkaptonuria

Nervous Friedrich ataxia

Spinal muscular atrophy

X-Linked

Recessive

Disorders.

•All sex-linked disorders are X-linked,

and almost all are recessive

•Usually expressed only in males

•Rarely, due to random X-inactivation,

a female will express disease,

called manifesting heterozygotes.

Pattern Of Inheritance:

• Disease usually passed on from carrier mother.

• Expressed in male offspring, females are carriers.

• Skipped generations are commonly seen.

• In this case, Recurrence risk is half of sons are affected, half of the daughters are carriers.

• Recurrence risk:

• All the daughters

are heterozygous

carriers and all the

sons are

homozygous

normal.

X-linked Recessive Disorders Musculoskeletal Duchene muscular

dystrophy

Blood Hemophilia A and B

G6PD def.

Immune AgammaglobulinemiaWiskott- aldrich syndrome

Metabolic Diabetes insipidus

Lesch-nyhan syndrome

DISORDERS WITH MULTIFACTORIAL

(POLYGENIC)INHERITANCE

Involved in many physiologic characteristics

of humans e.g. height, weight, hair color

Defined as one governed by additive effect

of two or more genes of small effect but

conditioned by environmental, non genetic

influences

COMMON DISEASES ASSOCIATED:

•Diabetes mellitus

•Hypertension

•Gout

•Cleft lip and palate

•Schizophrenia

•Bipolar disorder

•Congenital heart disease

•Skeletal abnormalities

•Neural tube defects

•Coronary artery disease

Cytogenetic

Disorders.

•Cytogenetic disorders may result from

structural or numeric abnormalities of

chromosomes

•It may affect autosomes or sex

chromosomes

Numeric Abnormalities

Normal Chromosomal number is 46. (2n=46). This is called euploid state. (Exact multiple of haploid number).

Polyploidy: posession of more than two sets of homologous chromosomes. Chromosomal numbers like 3n or 4n. (Incompatible with life); generally results in spontaneous abortion

Aneuploidy: Any Chromosomal number that is not an exact multiple of haploid number . E.g 47 or 45.

Aneuploidy

Most common cause is nondisjunction of

either a pair of homologous chromosomes

during meiosis I or failure of sister

chromatids to separate during meiosis II.

The resultant gamete will have either one

less chromosome or one extra

chromosome.

Fertilization of such gamete by normal

gemete will result in zygote being either

trisomic ( 2n+1 ) or monosomic ( 2n-1 ).

Monosomy in autosomes is generally

incompatible with life. Trisomy of certain

autosomes and monosomy of sex

chromosomes is compatible with life.

Mosaicism

The presence of two or more types of cell populations in the same individual.

Postzygotic mitotic nondisjunction will result in one trisomic and one monosomic daughter cell.

The descendants of these cells will produce a mosaic.

Structural abnormalities

Usually result from chromosomal breakage, resulting in loss or rearrangement of genetic material.

Patterns of breakage:

• Translocation.

• Isochromosomes.

• Deletion.

• Inversions.

• Ring Chromosomes.

Translocation

Transfer of a part of one chromosome to

another chromosome

Translocations are indicated by t

E.g. 46,XX,t(2;5)(q31;p14)

Balanced reciprocal translocation is not

harmful to the carrier, however during

gametogenesis, abnormal gametes are

formed, resulting in abnormal zygotes

ISOCHROMOSOMES

Result when one arm of a chromosome is lost and the

remaining arm is duplicated, resulting in a

chromosome consisting of two short arms only or of

two long arms.

DELETION

Loss of a portion of chromosome

This can be terminal (close to the end of the

chromosome on the long arm or the short arm), or it

can be interstitial (within the long arm or the short

arm).

A ring chromosome is a variant of deletion.It occurs

when break occurs at both the ends of chromosome

with fusion of the damaged ends.

INVERSIONS

Occur when there are two breaks within a

single chromosome with inverted

reincorporation of the segment.

Since there is no loss or gain of chromosomal

material, inversion carriers are normal.

An inversion is paracentric if the inverted

segment is on the long arm or the short arm .

The inversion is pericentric if breaks occur

on both the short arm and the long arm .

General Features of Cytogenetic

Disorders:

Associated with absence, excess, or abnormal rearrangements of chromosomes.

Loss of genetic material produces more severe defects than does gain.

Abormalities of sex chromosomes generally tolerated better than those of autosomes.

Cytogenetic Disorders

involving Autosomes.

Trisomy 21/Down’s Syndrome:

Most common chromosomal disorder and a

major cause of mental retardation.

Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 21st

chromosome

Trisomy 21 is mostly caused by a meiotic nondisjunction event.

•With nondisjunction, a gamete (i.e., a sperm or egg

cell) is produced with an extra copy of chromosome

21; the gamete thus has 24 chromosomes

•When combined with a normal gamete from the

other parent, the embryo now has 47 chromosomes,

with three copies of chromosome 21.

•About 4% of cases are due to Robertsonian

translocations.

•Maternal age has a strong influence on incidence.

Some feature of Down syndrome

•Mental Retardation

•Epicanthic folds

•Oblique palpebral fissure

•Simian crease

•Hypotonia

•Sandle gap

•Umblical hernia

Patau syndrome(13)

Edward syndrome(18)

Cytogenetic

Disorders

involving

SexChromosomes.

Klinefelter’s Syndrome:

Defined as Male Hypogonadism, develops

when there are at least two X chromosomes

and one or more Y chromosomes.

Usual karyotype is 47,XXY. The extra X

may be maternal or paternal.

• One of the most common cause of

hypogonadism in the Males

• The mean IQ is somewhat lower than

normal, but mental retardation is un-

common

Clinical Manifestations:

Increase in body length between soles and pubis.

Reduced facial, body and pubic hair. Gynecomastia.

Testicular atrophy.

Infertility.

Mild mental retardation.

Turner syndrome

Primary hypogonadism in phenotypic

females.

Results from partial or complete

monosomy of the X chromosome.

•Most common cause is absence of

one X chromosome.

•Less commonly, mosaicism, or

deletions on the short arm of the X

chromosome.

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