Over the last few decades a significant transition has taken place in the etiology of diseases affecting mankind Environmentally related disorders have decreased amp genetic disorders amp noncommunicable disorders have become a major cause of morbidity and mortality ID: 928377
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Slide1
MEDICAL GENETICS
Slide2INTRODUCTION
Over the last few decades, a significant transition has taken place in the etiology of diseases affecting mankind
Environmentally related disorders have decreased & genetic disorders & non-communicable disorders have become a major cause of morbidity and mortality
Over 2300 hereditary diseases have been identified
Diseases with genetic component account for 25-40% of all cases treated by health services
Slide3BURDEN OF GENETIC DISEASES
Each year more than 3 million children born with a serious genetic defect die; most of these deaths (90%) occur in developing countries
In the western world, there is 1% chance of having an inherited disease at birth
Prevalence of genetic disorders (excluding
multifactorial
genetic disease)-7/1000 live births
Out of 7,
-4 Sex linked disorders
-2
Autosomal
disorders
-others due to chromosomal rearrangements
Slide4HIGH PREVALENCE IN INDIA
Consanguineous marriages
High birth rate
Poor governmental support facilities
Lack of expertise in genetic counseling
Lack of improved diagnostic facilities
Slide5WHAT IS GENETICS
Study of inheritance dealing with the transmission of hereditary characters from one generation to another
Human genetics is concerned with the inheritance of human traits & their relationship to human health
Helps in better understanding of endogenous factors in health & disease
Provides key to their prevention & control
Slide6CHROMOSOMES
Chromatin:
DNA, RNA & proteins that make up chromosome
Chromatids
:
One of the two identical parts of the chromosome
Centromere
:
The point where two
chromatids
attach46 chromosomes; 22 pairs Autosomes and 1 pair Sex chromosomes (XX or XY)
Slide7Chromosomes vary in length; Each pair is homologous
Autosomes
are numbered according to length; first pair longest & last shortest
Sex chromosomes are not included in numbering; termed X & Y
Autosomes
divided into 7 groups from Group A to Group G; X in Group C & Y in Group G
Chromosomal study:
Buccal
smears, peripheral blood, bone marrow, skin, testis, cell culture, fluorescent staining
Slide8CELL DIVISION
Slide9GENE: UNIT OF HEREDITY
Gene hold the information to build and maintain their cells and pass genetic traits to offspring
Humans inherit 50,000 genes from father & 50,000 from mother
Occupy a specific position or locus on chromosomes e.g. ABO blood group
C
hromosome 9 MHC complex
Chromosome 6
Genes like chromosome occur in pairs
Genotype versus Phenotype
Slide10Allele
is one member of a pair of a gene
Homozygous:
2 copies of genes are identical i.e. have same alleles (AA or
aa
)
Heterozygous:
Has different alleles of the gene (
Aa
)
Dominant gene:
Manifests both in heterozygous & homozygous state
Recessive gene:
Manifests only in homozygous state
Multiple or polygene:
Three or four forms of a gene code for a single trait e.g. Blood group, skin type, eye
color
, hair
color
Penetrance
:
Extent to which a genetically determined condition is expressed in an individual
Slide11CHROMOSOMAL ABNORMALITIES
1. Non-disjunction:
Chromosome fail to separate & both are carried to one pole
May occur during mitosis & meiosis
The resultant gamete will have either one less chromosome or one extra chromosome k/a
aneuploidy
Fertilization of such gamete will result in zygote being either
trisomic
(2
n
+1) or
monosomic (2n-1)Monosomy in autosomes is incompatible with life
2.Translocation:Transfer of a part of one chromosome to another non-homologous chromosome during nuclear division
Slide123. Deletion:
Loss of a portion of chromosome resulting in loss of one or more genes
4. Duplication:
Some genes may appear twice in same chromosome
5. Inversion:
Occur when there are two breaks within a single chromosome with inverted reincorporation of the segment
6.
Isochromosome
:
One arm of a chromosome is lost and the remaining arm is duplicated, resulting in abnormal chromosome
7.
Mosaicism:The presence of two or more types of cell populations in the same individual
Slide13Slide14LAWS OF INHERITANCE
1. Law of unit characters:
All characters are unit by themselves & genes control their expression
2. Law of dominance:
Genes occur in pair
One factor (dominant) may mask the other factor (recessive)
3. Law of segregation:
When germ cells are formed, the opposed factors are separated or segregated so each germ cell carries one or other factors but not both factors
Slide15CLASSIFICATION OF GENETIC DISORDERS
Chromosomal abnormalities
Unifactorial
(Monogenic or
Mendelian
) disorders
Multifactorial
disorders
Slide16CHROMOSOMAL DISORDERS
More than 300 numerical & structural types of chromosomal aberrations
Incidence: 5.6/1000 live births
Out of 5.6
2/1000 live births Sex
aneuploid
1.7/1000
Autosomal
aneuploid
1.9/1000 Chromosomal translocation
1. Relating to sex chromosomes:
a. Klinefelter’s Syndrome:Defined as Male hypogonadism
; two or more X chromosomes in
addition to Y chromosome (
XXY, XXXY
)
The extra X may be maternal or paternal; 1 in 1000 males at birth
Slide17Results from
nondisjunction
of sex
chromosome during meiosis
C/F:
Increase in body length between soles and pubis, reduced facial, body and pubic hair,
g
ynecomastia
, t
esticular atrophy, infertility
, mild mental retardationb. XYY syndrome:Male with extra Y chromosome; 1 in 1000 male at birthAnti-social, aggressive & criminal behaviorExceptional height with personality disorderc. Turner Syndrome:
Most common disorder98% conceptuses abort spontaneously; remaining 2% at risk of dying in neonatal period; 1 in 7500 live born girls
Slide18Primary hypogonadism
in phenotypic females
Partial or complete
monosomy
of the X chromosome; X0
C/F:
Short stature (less than 5 feet), primary amenorrhea,
low estrogen levels,
maldevelopment
of the ovaries, sterility,
webbing of neck, wide-spaced nipples, cardiovascular
problems, mental retardationd. Super females:Females with 3 to 5 X- chromosomes (XXX, XXXX etc)Higher the number of X-chromosome, the greater the degree
of mental retardation & congenital abnormalities, e.g., underdeveloped external genitalia, uterus & vagina
Slide192. Relating to
autosomes
:
Down’s Syndrome or Mongolism:
Incidence: 1 in 900 births
Extra chromosome on the 21
st
pair of chromosome
Trisomy
21 is caused by a meiotic non-disjunction event
Frequency increases with rising maternal age
C/F: Short stature, small round head, narrow, tilted eye-slits, mal-formed ears, short broad hands, lax limbs, mental retardation, cardiac defects & atresia of alimentary tract
Autosomal monosomies are rare
Slide20MENDELIAN DISORDERS
Following patterns of inheritance are observed:
Autosomal
dominant
Autosomal
recessive
X-linked dominant
X-linked recessive
Mendelian
diseases are rare since there is strong selection against them and gene mutations are rare events
Slide21AUTOSOMAL DOMINANT
Affected males and females appear in each generation of the pedigree
Affected mothers and fathers transmit the phenotype to both sons and daughters
e.g., Neurofibromatosis, Adult polycystic kidney disease, ABO blood group
Slide22AUTOSOMAL RECESSIVE
The disease appears in male and female children of unaffected parents
When both parents are heterozygous
e.g., Cystic Fibrosis,
Phenylketonuria
,
Haemoglobinopathies
Slide23X-LINKED DOMINANT
Affected males pass the disorder to all daughters but to none of their sons
Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters
e.g.
Vitamin D resistant rickets, Familial
hypophosphatemia
Slide24X-LINKED RECESSIVE
Many more males than females show the disorder
All the daughters of an affected male are “carriers”
None of the sons of an affected male show the disorder or are carriers
e.g., Hemophilia A and B,
Colour
blindness
Slide25CO-DOMINANT INHERITANCE
Two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein
Both alleles influence the genetic trait or determine the characteristics of the genetic condition
E.g. ABO locus
Slide26Sickle Cell Disease
The allele is
codominant
with the normal allele
A person with one recessive and one dominant allele
will produce half normal blood cells, half sickle
A person with two recessive alleles will produce only
sickle cell
Hemophilia
It is a sex-linked recessive disorder, found on the X
chromosome
Cystic Fibrosis
It is caused by a recessive allele on one chromosome
The recessive allele is a mutation where strands of DNA
are deleted
Slide27MULTIFACTORIAL DISORDERS
More common than
Mendelian
and chromosomal disorders
Influence of multiple genes and environmental factors
Suspicion of inherited predisposition:
Early onset
Similarly affected parents/siblings
Difference in frequency between sexes
Occurrence in less commonly affected sex
Include mainly the non-communicable diseases
Diabetes mellitus, Hypertension
Cardiovascular diseases, Cancers
Slide28MANY DISEASES HAVE A GENETIC COMPONENT
Totally
Genetic
Totally
Environmental
Struck
by
lightning
Motor
vehicle
accident
Duchenne
muscular
dystrophy
Cystic
fibrosis
Heart
disease
Cancer
Schizophrenia
Diabetes
Obesity
Asthma
Rheumatoid
arthritis
PKU
Alzheimers
Fragile X
Autism
TB
Meningococcus
Multiple
sclerosis
Slide29Thank you