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Genetic disorders

Genetic disorders. Dr.K.V.Bharathi. Normal karyotype. Study of chromosomes karyotyping A karyotype is the standard arrangement of a photographed, stained chromosomes pairs which are arranged in order of decreasing length. When chromosomes are preparing to divide, the DNA

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Genetic disorders

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  1. Genetic disorders Dr.K.V.Bharathi

  2. Normal karyotype • Study of chromosomeskaryotyping • A karyotype is the standard arrangement of a photographed, stained chromosomes pairs which are arranged in order of decreasing length

  3. When chromosomes are preparing to divide, the DNA replicates itself into two strands called chromatids Replicating chromosome The same chromosome under normal conditions Telomere Centromere The two chromatids Telomere

  4. Chromosome nomenclature • Two arms • p (petite) small and q (follows p in alphabet) • 1-22 = autosome numbers • X, Y = sex chromosomes

  5. Cytogenetic terminology • Short arm p and long arm q • Each Chromosome is divided into 2 or more regions • Each region is subdivided into bands and sub-bands • Total no of chromosomes is given first followed by sex chromosome and finally description of abnormality in ascending order.eg:47,XY,+21 ,and Xp 21.2 • 46,XY,del(16)(p11.2 p13.1)

  6. The normal human karyotype • Somatic cells: 22 pairs of autososmes & 1 pair of sex chromosomes (46,XX or 46,XY). • The normal karyotype is diploid (2 copies of each chromosome). • Sperm & eggs carry 23 chromosomes & are haploid (one copy of each chromosome).

  7. What is the difference between an Autosome and a Sex-chromosome? • Autosomes are the first 22 homologous pairs of human chromosomes that do not influence the sex of an individual. • Sex Chromosomes are the 23rd pair of chromosomes that determine the sex of an individual.

  8. Sperm determines genotypic sex by contributing either an X or a Y chromosome during fertilization.

  9. 46,XX = female 46,XY = male Giemsa banding (G-banding)

  10. Three classes of chromosome • Metacentric - centromere in middle • Submetacentric - centromere distant from middle • Acrocentric - centromere at end

  11. Uses of karyotype analysis: • Genotypic sex ( identification of X & Y chromosomes). • Ploidy ( euploid, aneuploid or polyploid). • Chromosomal structural defects (translocation, isochromosome, deletion etc..).

  12. Some definitions • Haploid (n)- refers to a single set of chromosomes (23 in humans).Sperm & eggs are haploid. • Diploid (2n)- refers to a double set of chromosomes (46 in humans). Somatic cells are diploid. • Euploid- refers to any multiple of the haploid set of chromosomes (from n-8n)

  13. Polyploid- refers to any multiple of the haploid set of chromosomes> diploid (2n). • Aneuploid- refers to karyotypes that do not have multiples of the haploid set of chromosomes. • Monosomy- refers to an aneuploid karyotype with one missing chromosome (XO in Turner’s syndrome). • Trisomy- refers to an aneuploid karyotype with one extra chromosome (trisomy 21 in Down’s syndrome))

  14. Aneuploidy results from the failure of chromosomes to separate normally during cell division: Meiotic Nondisjunction

  15. 4N First meiotic division NORMAL SEPARATION 2N Second meiotic division N Gametes Fertilization 2N Zygotes NORMAL ZYGOTE

  16. First meiotic division NONDISJUNCTION Second meiotic division Gametes Fertilization Zygotes TRISOMIC ZYGOTE MONOSOMIC ZYGOTE

  17. Aneuploidy usually results from non-disjunction • Chromosomes or chromatids fails to separate • An error of mitotic or meiotic spindle attachment to centromere • May occur in either the maternal or the paternal germ cells • More commonly arises in the mother • Frequency of non-disjunction increases with maternal age

  18. Structural abnormalities of chromosomes

  19. Six main types • Deletion • Ring chromosome • Duplication • Isochromosome • Inversion • paracentric & pericentric • Translocation • Robertsonian & reciprocal

  20. Deletion • Involves loss of part of a chromosome • Results in monosomy of that chromosomal segment • Clinical effects due to • Insufficient gene products • Unmasking of mutant alleles on normal chromosome Before deletion After deletion

  21. Two types of deletion Terminal Interstitial

  22. Ring chromosomeBreaks occur in both arms of a chromosome. The two broken ends anneal; the two acentric fragments are lost. Results in double deletion (in p and in q).

  23. Epilepsy, mental retardation and craniofacial abnormalities

  24. Isochromosome Mirror image chromosome Loss of one arm with duplication of other Loss of p-arm Duplication of q-arm

  25. Inversion Two breaks in one chromosome The fragment generated rotates 180o and reinserts into the chromosome Pericentric - involves p and q arm Paracentric - involves only one arm

  26. Translocation - exchange of chromosomal material between two or more chromosomes • Reciprocal • Robertsonian • If no essential chromosome material lost or genes damaged then the individual is clinically normal • However, there is an increased chance of chromosomally unbalanced offspring

  27. Reciprocal Translocation • Involves two chromosomes • One break in each chromosome • The two chromosomes exchangebroken segments Before translocation After translocation

  28. Robertsonian translocation • Named after W. R. B. Robertson who first identified them in grasshoppers in 1916 • Most common structural chromosome abnormality in humans • Frequency = 1/1000 livebirths • Involves two acrocentric chromosomes • Two types • Homologous acrocentrics involved • Non-Homologous acrocentrics involved

  29. Homologous acrocentric, i.e. chromosome 14 lost + = Non-homologous acrocentric, i.e. chromosomes 14 & 21 lost + =

  30. A balanced chromosome 14 & 21 Robertsonian translocation

  31. Mutations

  32. What is mutation? • A mutation may be defined as a permanent change in the DNA. • These structural DNA changes affect protein expression & function.

  33. Mutations affect protein synthesis Transcription:Mutated DNA will produce faulty mRNA leading to the production of a faulty protein.

  34. Somatic & Germ cell mutations Mutations that occur in somatic cells such as skin cells or hair are termed Somatic. Germline mutations occur only in the gametes. These mutations are more threatening because they can be passed to offspring .

  35. Germline mutations can be transmitted to future generations. • Those that occur in somatic cells may contribute to the pathogenesis of neoplasia. • Drugs, chemical & physical agents that increase the rate of mutation act as carcinogens.

  36. Mutagens are agents that cause mutations. They include: 1. High Temperatures 2. Toxic Chemicals (pesticides, etc) 3. Radiation (nuclear and solar)

  37. Types of mutations Chromosomal mutation: affecting whole or a part of a chromosome Gene mutation: changes to the bases in the DNA of one gene

  38. Major types of genetic mutations • Point mutations: Single base substitutions . • Frameshift mutations: base pair insertions or deletions that change the codon reading frame. • Large deletions: can result in loss of gene or juxtapose genes to create a hybrid that encodes a new “fusion” protein. • Expansion of trinucleotide repeats:can arise in genes that have repeated sequences. Affected patients can have 100s or 1000s of repeats (normal:10-30).

  39. Gene Mutations: DNA base alterations Point mutation- eg:sickle cell anemia Insertion Deletion Inversion Frame Shifts

  40. Point mutation - when a base is replaced with a different base. CGG CCC AAT to CGG CGC AATGuanine for Cytosine Insertion - when a base is added CGG CCC AAT to CGG CGC CAA TGuanine is added Deletion - the loss of a base CGG CCC AAT to CGG CCA A T loss of Cytosine

  41. Frame Shift mutations • A frame shift mutation results from a base deletion or insertion. Each of these changes the triplets that follow the mutation. CGG CCC AAT to CGG CGC CAA T • Frame shift mutations have greater effects than a point mutation because they involve more triplets. • This in turn changes the amino acids of the protein!

  42. Classification of genetic disorders 1.Gross chromosomal abnormalities 2.Diseases with multifactorial inheritance 3.Disorders related to mutant genes of large effect

  43. Cytogenetic disorders involving autosomes

  44. Common types of trisomy

  45. Trisomy 21 - Down's Syndrome - karyotype 47, XX +21 or 47, XY+21 - frequency about 1 in 600 births

  46. Trisomy 18 - Edward's Syndrome • - karyotype 47, XX +18 or 47, XY+18 • - frequency about 1 in 8,000births

  47. Trisomy 13 - Patau's Syndrome • - karyotype 47, XX +13 or 47, XY+13 • - frequency about 1 in 10,000 births

  48. Sex chromosome trisomies • - 47, XXY (Klinefelter Syndrome), 47,XXX, 47,XYY • Triploidies of other chromosomes • Rare • usually incompatible with life

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