A hereditary disease may be due
to chromosomal or genetic disorder
Genetic principles
*A Gene is a
segment of DNA molecule that codes for the synthesis of a single polypeptide
and
* contains the hereditary
information needed for development or function.
*DNA is composed of two
long strands twisted around each other to form a double helix.
DNA and RNA structure
·
The linear backbone of DNA (deoxyribonucleic acid)
and RNA (ribonucleic acid) consists of sugar units linked
by phosphate.
·
A nitrogenous base is attached to a sugar and
phosphate group to form a nucleotide that constitutes the basic repeat unit of
the DNA and RNA strands.
·
The bases are
divided into two classes: purines and pyramidines.
·
In DNA: the
purines bases are adenosine (A)and guanine (G), and the pyramidine bases are
cytosine (C) and thymine (T).
·
The order of
the bases along the molecule constitutes the genetic code in which the coding
unit, consists of three nucleotides.
·
In RNA the arrangement of bases is the same except
that thymine (T) is replaced by uracil (U).Fig
( 1 )
*Each
nucleotide is composed of one purine of and
one pyramidine base joind by hydrogen bonds.
.: The specific order of the nucleotides determines
the precise information that will be coded at that site.
Chromosomes
* With the exception of some highly differentiated cells as the neurons,
all the cells of the body can divide into two identical cells.
* In
humans, normal somatic cells contain 46 chromosomes ( diploid number), of which
44 are termed autosomes and two are sex chromosomes.
* Females
have two X chromosomes (XX) and males have an X and a Y chromosomes (XY).
* Gametes;
eggs and sperms, contain 23 chromosomes ( haploid number ) In the zygote and somatic cells , chromosomes
are paired ( homologs).
*In each
pair , one homolog is maternal and the other is paternal in origin. Each
chromosomal pair has unique morphologic characteristics such as size , position
of centromere and the unique banding pattern that is demonstrated by special
techniques.
Fig ( ) normal karyotype of female 46 XX
* To pass on the genetic information to
daughter cells, the chromosomes must replicate and then divide correctly.
There
are two types of cell division:
1) Mitosis
in which somatic cells replicate and then divide chromosomal material ( DNA )
into two genetically identical daughter cells with 46 chromosomes each. Fig
( )
2) Meiosis : occur in the germinal cells which is different from
mitotic division in that daughter cells contain the haploid number of
chromosomes (23) and crossing over
or recombination between two homologs
occurs thus facilitating genetic variation in offspring. Fig ( )
Chromosomal disorders:
Approximately 0.5 % - 0.7%
of all live newborns and 4% - 7% of
perinatal deaths are the result of chromosomal abnormality.
Chromosomal aberrations should be suspected in any of the following
situations:
·
Small for gestational age for
weight , length and/or head circumference.
·
Presence of one or more
congenital malformation.
·
Presence of dysmorphic
features.
·
Neurologic/neuromuscular
dysfunction.
·
Family history of multiple
miscarriages or siblings with mental retardation or birth defects.
Chromosomal abnormalities can be classified into two major categories :
abnormalities of chromosomal number ( aneuploidy ) , in
which there is an extra or missing chromosome, and abnormalities of chromosome structure
that result in the loss or duplication of part of the chromosomal
material.
Abnormalities
of chromosome number
Numeric chromosomal abnormalities occur as a result of nondisjunction in
which there is loss or gain of one or more chromosome.
Nondisjunction occur during either meiosis or
mitosis, resulting in an abnormal gamete ( egg or sperm )or abnormal somatic
cell, respectively.
Fertilization of an aneuploid gamete by a normal
gamete produces a zygote with an extra chromosome ( triosomy ) or missing
chromosome ( monosomy ) .
Aneuploidy in somatic cells ( after zygote
formation ) results in chromosomal mosaicism ( i.e. the presence of some
cells with the normal number and other
cells with an abnormal number of
Fig ( ) Nondisjunction of chromosome 21 leading to Down
syndrome
* Although nondisjunction may affect any chromosomal pair the most
commonly recognized triosomies in liveborns are triosomy 21 ( Down's Syndrome)
and the most common monosomy is 45x, Turner syndrome.
Abnormalities of chromosomal
structure:
Structural abnormalities have been described in all chromosomes. These
include deletions , duplications, inversion and translocation.
·
Deletion is a loss of
chromosomal material and results in partial monosomy for the chromosome
involved.
·
Duplication is the presence of additional chromosomal material
or partial triosomy
·
Inversions are the
result of a double break in a single
chromosome with reinsertion of the chromosomal material that has been inverted.
- Translocation is the detachment of a chromosome segment from its normal location and its attachment to another chromosome. The translocation is balanced if the cell contains two complete copies of all chromosomal material although in different order. In an unbalanced the rearrangement results in partial triosomy or monosomy. Translocations can be reciprocal or Robertsonian A reciprocal translocation involves exchange of segments between two chromosomes (e.g., part of the short arm of the chromosome 4 takes a place with apart of chromosome 10)
Robertsonian translocations involve
two acrocenteric chromosomes fused at there
centromere e.g chromosome 14 and 21 fig ( ) as in Down syndrome
Down syndrome
has an incidence of 1in 600 live births. Approximately 95% of cases are due to
non disjunction involving chromosome 21, 5% are caused by translocation and 1%
have a mosaicim
Fig ( )
Possibilities for offspring of a 14;21 Robertsonian translocation
carrier
Down’s
sundrome
The classic phenotype of Down syndrome
include a flattened occiput, midfacial hypoplasia, depressed nasal bridge,
upward Slanting palpebral fissures, epicanthic folds , grayish speckling of the
iris (Brushfield spots). Micrognathia excess nuchal skin, single palmer
creases(simian creases), single flexion creases and incurving of the fifth
fingers (clinodactyly) and increased distance between the first and second
toes. Down syndrome may present with marked hypotonia ;congenital heart defects,
duodenal atresia and tracheoesophageal fistula. However it is imperative that
cytogenetic studies be done to confirm the diagnosis and to differentiate a
nondisjunctional triosomy from translocation .In case of translocation Down
syndrome karyotyping is indicated for
parents to detect balanced translocation carrier .
Recurrence
risk of Down syndrome
The
risk increases sharply when the mothers age is above 35 years for the non
disjunction group (age-dependent) ,
affected females who become pregnant have a
high risk (30–50%) of having a Down syndrome child .
The translocation group is usually age
independent specially if it is familial translocation.
However ,the recurrence risk of Down syndrome
is high if the mother is a translocation carrier, such a condition there is one
in three risk of having an effected child at any one pregnancy .
Modes of inheritance
genes at the same locus on a pair
of homologous chromosomes are alleles, Homologous has identical members of pair
alleles while heterozygous has tow different alleles.
The patterns are determined by whether the gene is autosomal or sex
linked ,whether it is recessive or dominant.
I . Autosomal inheritance
1)
Autosomal Dominant : Fig ( )
1-
Every
affected person has an affected parent
2-
The
traits appears in every generation
3-
Transmission
of trait is not influenced by six or Consanguinity of the parents
Fig ( ) Offspring : 50% affected ,50 % not Ex:
osteogenesis imperfecta peroneal muscular dystrophy, huntingtons
2) Autosomal recessive: Fig ( )
Autosomal recessive inheritance is characterized by
1-
Males
and females are equally affected.
2- Both parents of affected child are carriers of
the affected gene the parents may be consanguineous.
2-
the
trait appears in sibs of the patient not in his parents or offspring
Fig ( ) 50% carrier, 25%
affected ,25% normal Ex : Werding Hoffman’s, cystic fibrosis , limb-girdle
muscular dystrophy.
II.
Sex linked inheritance
In which the genes are on the X chromosome . A male has
only one representative of any X linked gene (hemizygous). A female can be
homozygous or heterozygous sex linked may be recessive or dominant.
A)
sex – linked recessive inheritance is characterized by
1-The trait is expressed by all males who carry
the gene but females are affected only if they are homozygous
2-The trait is never transmitted from a father to
his son
3- An affected male passes the gene through all
his daughters to half their sons who become diseased and half their daughters
who become carriers. Examples of X- linked recessive trait are : Hemophilia Duchenne muscular dystrophy,
color blindness & G6PD fig ( )
A) sex – linked recessive inheritance is
characterized by
1-The trait is expressed by all males who carry
the gene but females are affected only if they are homozygous
2-The trait is never transmitted from a father to
his son
3- An affected male passes the gene through all
his daughters to half their sons who become diseased and half their daughters
who become carriers. Examples of X- linked recessive trait are : Hemophilia Duchenne muscular dystrophy,
color blindness & G6PD fig ( )
|
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Xh
|
y
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X
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XhX
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xy
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X
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XhX
|
Xy
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Normal
mother & affected father : Daughters
100% carriers , sons 100 % normal
|
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X
|
y
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Xh
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XhX
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Xh y
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X
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Xx
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Xy
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Fig ( ) X linked recessive (
Carrier female)
Daughters
50% carriers , sons 50% affected 50%
normal
B. Sex linked
Dominated inheritance shows the following characteristics
1-
Affected
males transmit the trait to all their daughters but non of their sons
2-
Heterozygous
females express the trait.
3-
Affected
females ( homozygous or heterozygous ) transmit the trait to all their children
of either sex Fig ( )
|
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Xh
|
y
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X
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Xhx
|
xy
|
|
X
|
Xhx
|
Xy
|
|
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X
|
y
|
|
Xh
|
Xhx
|
xhy
|
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X
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Xx
|
Xy
|
Fig ( )
Daughters
100% affected Daughters 50 % affected
Sons
100% normal
Sons 50% affected
Inheritance of x-linked dominant trait (h)
An Example is :Xg blood group system.
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