Dr . Muhammad RafiqueAssist. Prof. PaediatricsCollege of MedicineK K U Abha K S A

HUMAN GENETICS

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

• 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 material1-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.’srisk 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: 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, non- disjunction , 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.• Incidence-1:500 in live borns.• Inherited from parent /de novo.• usually phenotypically normal.• 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 incorporatedInto 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

• 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

• 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

• 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.