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 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 bands. Each band has specific serial No. E.g. William Synd. due to deletion at 7q11.23 means disease gene at band 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). 1 st degree relative (parents, siblings and children) share ½ genetic information. 1 st 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 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 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 2 nd X chr. 50% pt. have(45,X0) and 50% are mosaic % 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.