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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