MEDICAL GENETICS INTRODUCTION - PowerPoint Presentation

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MEDICAL GENETICS

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INTRODUCTION

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

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BURDEN 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

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HIGH PREVALENCE IN INDIA

Consanguineous marriages

High birth rate

Poor governmental support facilities

Lack of expertise in genetic counseling

Lack of improved diagnostic facilities

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WHAT 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

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CHROMOSOMES

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)

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Chromosomes 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

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CELL DIVISION

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GENE: 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

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Allele

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

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CHROMOSOMAL 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

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3. 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

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LAWS 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

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CLASSIFICATION OF GENETIC DISORDERS

Chromosomal abnormalities

Unifactorial

(Monogenic or

Mendelian

) disorders

Multifactorial

disorders

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CHROMOSOMAL 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

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Results 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

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Primary 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

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2. 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

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MENDELIAN 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

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AUTOSOMAL 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

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AUTOSOMAL RECESSIVE

The disease appears in male and female children of unaffected parents

When both parents are heterozygous

e.g., Cystic Fibrosis,

Phenylketonuria

,

Haemoglobinopathies

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X-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

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X-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

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CO-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

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Sickle 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

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MULTIFACTORIAL 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

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MANY 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

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Thank you