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GENETIC DISEASES

When Faulty Blueprints are Copied

Dr.Mohit Shahi, MD

Genetic disorders
Related to mutant genes of large effect Mendelian disorders With multifactorial inheritance Diabetes, Htn Arising from chromosomal aberrations numerical or structural abnormalities

GENETIC DISORDERS
Mendelian disorders

Mendelian disorders
Caused by single gene defects 1% of adult and 6-8% of pediatric admissions Patterns of inheritance AD, AR, XL

Pleiotropism Single mutation Multiple effects e.g.HbS, Marfan syndrome Genetic heterogeneity Multiple mutation Single effect. Retinitis pigmentosa, Childhood deafness

Transmission patterns
Autosomal Dominant Disorders Heterozygous state Both males and females 1 in 2 chance of having the disease Some patients do not have affected parents (New mutation) Clinical features modified by reduced penetrance and variable expressivity

Reduced Penetrance - Inherit the mutant gene, but phenotypically normal. Variable expressivity Trait present in all the individuals with mutant gene, but different expression of phenotype. E.g. NF 1 Delayed age of onset. E.g. Huntigtons Ds

AUTOSOMAL DOMINANT PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS NOT SKIPPED

AUTOSOMAL RECESSIVE DISORDERS Most common of mendelian disorders Both alleles are mutants Parents unaffected but siblings diseased 1 in 4 chance Consanguinity increases the risk Early onset Enzyme proteins are affected (Inborn errors of metabolism) UNIFORM EXPRESSION COMPLETE PENETRANCE

AUTOSOMAL RECESSIVE PEDIGREE

1) BOTH SEXES INVOLVED 2) GENERATIONS

SKIPPED

X-LINKED DISORDERS All sex linked disorders are X-linked Almost all XLR No Y-Linked Transmitted by heterozygous female carriers only to sons Only MALES His Sons are OK Daughters are carriers Y-chromosome Hypertrichosis XLD Vitamin D resistant rickets

SEX LINKED PEDIGREE

1) MALES ONLY
2) GENERATION SKIPPING DOESNT MATTER

KARYOTYPING
A karyotype is a photographic representation of a stained metaphase spread in which the chromosomes are arranged in order of decreasing length Procedure Arrest mitosis in METAPHASE by mitotic spindle inhibitors (eg Colcemid) and stain them. Staining Giemsa stain, hence GBANDING. Arranged in order of decreasing length. Photographed and imaged. Resolution can be improved by obtaining cells in prophase. Downs syndrome 47, XY, +21. p short arm (petit), q long arm (next letter)

Xp21.2
Sub-band

Chromosome

Grouping of Chromosomes On G-Banding


Autosomes group A-G Grp-A Ch1, 2, 3 Grp-B Ch4 and 5 Grp-C Ch6-Ch12 Grp-D Ch13,14,15 Grp-E Ch16,17,18 Grp-F Ch19,20 Grp-G Ch2, 22 Sex chromosomes

FISH
DNA probes recognize chromosome specific sequence Labeled with fluorescent dyes and applied to interphase nuclei Demonstrate microdeletions, complex translocations, telomerase alterations, map newly isolated genes(dyes applied in metaphase) and compare the DNA content of differentially labeled normal & tumor cells (also in metaphase)- Comparative Genomic hybridisation. Spectral karyotyping (SKY) 5 fluorochromes are applied and entire human genome is visualized.

CYTOGENETIC DISORDERS
Abnormal number
Euploidy normal 46XX, 46XY Polyploidy 3n, 4n Aneuploidy Due to nondisjunction and anaphase lag, n+1 or n-1 2n+1, 2n-1 Mosaicism Mitotic errors giving rise to two or more populations of cells in same individual. More common in sex chromosomes.E.g. Fertilization error

Cytogenetic Disorders Involving Autosomes


Trisomy 21 Trisomy 13 Trisomy 18 Cri du Chat Prader-willi syndrome Angleman syndrome

Cytogenetic Disorders Involving Sex Chromosomes


Klinefelters syndrome Turners syndrome XXY males XXX females Fragile X syndrome

Disorders involving Autosomes DOWN SYNDROME Most common disorder Trisomy 21 95% MCC Meiotic nondisjunction Maternal age

Mental retardation Abundant neck skin, low set ears Epicanthic folds and flat face profile Simian crease Congenital heart defects Ostium primum, atrial septal defects(ASD), AV valve malformations, VSD Esophageal atresias, Small intestine stenosis Umbilical hernia Gap bw 1st and 2nd toe Hypotonia

40% have cong heart defects. MCC of death. 10-20 fold risk of AML,ALL. MC AML is M7 Older patients develop Alzheimer Ds. Predisposed to infections & thyroid autoimmunity

Trisomy 18 Edwards Syndrome

Trisomy 13 Patau syndrome

Cytogenetic Disorders Involving Sex Chromosomes


Klinefelters syndrome Turners syndrome XXY males XXX females Fragile X syndrome

Disorders involving Sex Chromosomes


45,X to 49,XXXXY, are compatible with life 2-3 Y Chromosomes (1) Lyonization of X Ch and (2) the small amount of genetic information carried by the Y Ch Male differentiation SRY Gene for male differentiation Higher the number of X chromosomes more the likelihood of Mental retardation

KLINEFELTER SYNDROME
Male hypogonadism with at least two X chromosomes and one or more Y chromosomes. Most patients are 47,XXY Nondisjunction Extra X Maternal / paternal Hypogonadism Elongated habitus Eunuchoid body habitus Reduced facial, body, and pubic hair and gynaecomastia

Testes reduced in size, Testicular atrophy

Sterility Impaired spermatogenesis, total azoospermia


Hyalinization of tubules, which appear as ghostlike structures in tissue section. Leydig cells are prominent

MR - Higher the number of X chromosomes more the likelihood of Mental retardation


Breast cancer (20 times), extragonadal germ cell tumors, and autoimmune diseases such as SLE

Turner Syndrome
Primary hypogonadism in phenotypic females, 45X

Identify the disorder?

Single gene disorders with atypical patterns of inheritance

Triple repeat mutations FRAGILE-X SYNDROME Mitochondrial gene mutations LEBER HEREDITARY OPTIC NEUROPATHY Genomic imprinting diseases PRADER-WILLI SYNDROME ANGELMAN SYNDROME

1. Triple repeat mutations: Fragile X syndrome


Mutations characterized by a long repeating sequence of three nucleotides. 2nd MCC of Mental retardation after Down S. Mutation in FMR-1 gene. Cytogenetic alteration Discontinuity in staining OR Constriction in the long arm of the X Ch. Culture Medium Folate deficient Medium. 80 Fragile sites. FRAGILE Chromosome appears broken

Features
MR IQ 20-60 Long face with large mandible, large ears. Macro-orchidism - Large testicles (In 90%). Hyperextensible joints. High arched palate, MV prolapse.

Discontinuity in staining Fragile site

THANK YOU!!!

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