Transcript Slide 1

Dr . Muhammad Rafique
Assist. Prof. Paediatrics
College of Medicine
K K U Abha K S A
HUMAN GENETICS
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Genetic disorders- common cause of diseases,
prolonged handicap and death in human.
1% newborns have monogenic diseases like
CF, SCD etc.
0.5% have chr. disorders like Down Synd.
1-3% have multifactorial disorders like CHD,
spina bifida.
40% deaths due to genetic disorders & birth
defects.
HUMAN CELLS
• Human genome has 25000 genes (basic unit).
• Human cell somatic / germ line (sperm/ovum)
• Each somatic cell has 23 pair of chromosomes
(diploid No.).
. 22 pairs of autosomes
. 1 pair of sex chr. (xx/xy).
• Germ line cell has 23 chromosome (haploid No.)
. 22 autosome
. 1 sex chromosome(X/Y).
CHROMOSOME
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Each chromosome has 2 chromatids .
Upper small arm “p” and lower large “q”.
Attached in center “ centromere ”.
Each p / q arm has 350-850 bands.
Each band has specific serial No.
E.g. William Synd. due to deletion at 7q11.23
means disease gene at band 11.23 of “q” arm
of chromosome 7.
Genotype/phenotype
• Genotype:
Genetic constitution of an individual.
• Phenotype:
Observed structural , biochemical and
physiological features of an individual.
MUTATION
Spontaneous change in genetic material
1-Gain function mutation;
over expression / inappropriate expression of
a gene product . Mostly produce AD disorder
e. g. achondroplasia.
2-Loss of function mutation;
observed in AR disorders, 50% enzyme activity
in hetrozygote- allow normal function e.g. SCD
FAMILY HISTORY
Most important screening tool to identify pt.’s
risk for development of variety of diseases.
. Multifactorial condition: Diabetes M .
cleft lip and palat, neural tube defects.
. Single gene disorders:like SCD, Cystic fibrosis
osteogenesis Imperfecta etc.
. Parents, siblings and offsprings share 1/2
genetic material & first cousins 1/8 .
PEDEGREE NOTATION
• It provides a graphic presentation of a family’s
structure & medical Hx.
• Arrow represents Information provider(proband).
• 1st degree relative (parents, siblings and children)
share ½ genetic information.
• 1st cousins share 1/8 genetic material.
ABNORMALITIES OF CHROMOSOME NO.
Euploidy:
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If a cell has No. of chr. exact multiple of 23.
n =23, haploid cell (ovum/sperm)
2n= 46, diploid cell (somatic cell)
3n= 69, triploid cell (2 sperm+1 ovum, nondisjunction , viable only in mosaic case).
. paternal origin—hydatidiform mole.
. maternal origin—spontaneously abort.
ANEUPLOIDY
Abnormal cell having no multiple of 23 chr.
. It is most common chr. abnormality.
. 3-4% pregnancies, only mosaic viable.
. Mostly due to non-disjunction.
. Monosomy e.g. Turner synd.(45,X0)
. Trisomy, most common e.g.21,18,13.
. Klinefelter synd.(47,XXY)
MITOSIS
• Somatic cells divide themselves to grow an organ.
• 4 stages. prophase
. metaphase
. anaphase
. telophase
• Duplication of DNA-divide to 2 daughter cells.
MEIOSIS
• In reproductive/germ line cells (sperm / ovum)
• In 2 rounds (meiosis 1 & 2) it completes.
• After duplication of DNA ,one germ line cell
(diploid No.=46 chromosome)divide into 4
( haploid No.23 chr.) gametes(ovum/sperm).
• Zygote formation (x + y) maintain diploid No.
ABNORMAL CHR. STRUCTURE
TRANSLOCATION:
Transfer of genetic material from one to
other chromosome.
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Incidence-1:500 in live borns.
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Inherited from parent /de novo.
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usually phenotypically normal.
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high chances of miscarriage/
chromosomically abnormal offspring.
INVERTION
A chromosome breaks at 2 points , broken piece
is inverted & joined into same chromosome.
• Incidence-1:100 live borns.
• Carriers are phenotypically normal.
• High chances of miscarriage/chromosomically
abnormal offspring .
DELETION / DUPLICATION
Deletion:
A piece of chromosome missing.
• Usually associated with mental retardation &
malformations.
• “5p-” (deletion at “p” arm of chromosome No.5)
Duplication:
Presence of extra gen. material from same chr.
INSERTION
A piece of chr. broken at 2 points is incorporated
Into a break in an other part of chromosome.
• 3 break points required.
• May occur between 2 or within same chr.
• Carrier have high risk of having offspring with
deletion or duplication of inserted segment.
• Incidence is rare.
ISOCHROMOSOME
Two copies of same chr. arm joined through a
single centromere forming mirror image of
one another.
RING CHROMOSOME
Both ends of a chr. are deleted and re-joined to
form a ring.
• Carrier are normal/nearly normal /may have
mental retardation & multiple congenital
anomalies.
SEX CHR. ABNORMALITIES
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Incidence- 1:400 in males & 1:650 in females.
Most common chr. abnormalities in live borns.
Numerical / structural.
Present in all cell / mosaic.
Carrier have few / no physical & developmental
problems.
TURNER SYNDROME
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Incidence- 1:5000 female live borns .
Partial / complete absence of 2nd X chr.
50% pt. have(45,X0) and 50% are mosaic.
95-99% of 45,X0 conceptions miscarried.
Phenotype-variable especially in mosaic pt.
Turner Syndrome
EDWARD SYNDROME (Trisomy 18)
POLYPLOIDY
Euploid cells having >diploid No.(2n=46) chr.
. Also called heteroploid cells.
. Usually conceptions not viable.
. Mosaic karyotypically normal line viable.
NOONAN SYNDROM
• AD disorder- 60% cause is new mutation.
• In both male/ female.
• Features almost same as in Turner Synd.
NOONA SYNDROME
KLINEFELTER SYNDROME
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80% are male with an extra X chr. (47,XXY).
Commonest cause of hypogonadism & infertility.
50% cause is paternal non-disjunction.
Secondary sex characters- delayed.
50% develop gynaecomastia.
Remained unidentified until puberty.
No intellect , show deficit in language.
MOSAICISM
Person with 2 > cell lines from single zygote.
• 2% in early pregnancy- chr. abnormal mosaic.
• Except trisomies 21,18,13, usually non viable.
• Mosaicism may be in some tissues only.
• Germ line /reproductive cells mosaicism
increase risk of recurrence in affected
children.