Genetic Disorders Pathology for Medicine students

Genetic Disorders for Medicine students.
Pathology Genetics.
Down's Syndrome.
Turner Syndrome.

1. Genetic Disorders Dr Guru Prasad Mainali, MD Consultant Pathologist

2. Relation between Chromosome, DNA and Gene

3. GENETICS – Study of Genes Genes – Present on Chromosome. Alleles – Two different set of genes acquired from parents. Normal genes- 2 alleles. Locus : The physical location of a gene on a chromosome. GENETICS

4. Autosomes – Not associated with determination of sex : 1 to 22 Sex Chromosomes : Associated with Sex Determination : X/Y Subtypes of Chromosomes ( Based on Sex Determination) :

5. Karyotyping  is the process by which a karyotype is discerned by determining the chromosome complement of an individual, including the number of chromosomes and any abnormalities. A karyotype is an individual's complete set of chromosomes.  Karyotyping

6. Colchicine is added to cultured cells to halt chromosomes in metaphase. Chromosomes are stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern. Banding : Chromosome banding is an essential technique used in chromosome karyotyping to identify normal and abnormal chromosomes for clinical and research purposes. Giemsa (G)-, reverse (R)-, and centromere (C)-banding are the most commonly dye-based chromosome-banding techniques Karyotyping

7. Can be performed on a sample of blood, bone marrow, amniotic fluid, or placental tissue. Used to diagnose chromosomal imbalances ( eg , autosomal trisomies , sex chromosome disorders). Karyotyping

8. Xp21.2 refers to a chromosomal segment located on the short arm of the X chromosome, in region 2, band 1, and sub-band 2.

9. Fluorescent In-situ Hybridisation Fluorescent DNA or RNA probe binds to specific gene or other site of interest on chromosomes. Used for specific localization of genes and direct visualization of chromosomal anomalies. FISH

10. Fluorescent In-situ Hybridisation

11. Chromosomal Disorders Single Gene Disorders Multifactorial ( Genes + Environmental) Genetic Disorders

12. Subdivided based on Number and structural defects. Number ( Diploid, Haploid, Aneuploid ) Structural Defects: Deletion Inversion Translocation Duplication Chromosomal Disorders

13. Classical Mendelian Inheritance Autosomal : Dominant Recessive Sex Chromosomal : X linked (Recessive/ Dominant ) Y linked Single Gene Disorders Non- Mendelian Inheritance Genomic Imprinting Mitochondrial Inheritance Trinucleotide Repeat Expansion Germline Mosaicism

14. Chromosomal Disorders

15. Structural Defects

16. Autosomal Trisomy : Trisomy 13 ( Patau Syndrome ) Trisomy 18 ( Edward Syndrome ) Trisomy 21 (Down Syndrome ) Down’s > Edwards > Patau Sex Chromosome Trisomy : XXY : Klinefelter Syndrome Trisomy - Aneuploidy

17. Monosomy : Autosomal : Most Dangerous ( No survival) Sex Chromosome : XO : Turner Syndrome ( Only monosomy that is compatible with life)

18. Down Syndrome(Trisomy 21) Specific Cytogenetic Disorders

19. Down syndrome is the most common of the autosomal chromosomal disorders and is a major cause of intellectual disability. It is due to the presence of inheritance of extra number of chromosome number 21. Therefore also known as ‘trisomy 21’. So their chromosome count is 47 INTRODUCTION:

20. The parents of such children have a normal karyotype and are normal in all respects. Most common cause of Down syndrome is meiotic nondisjunction.

21. Maternal age has a strong influence on the incidence of trisomy 21 Risk Factor: It occurs once in 1550 live births in women under age 20, in contrast to 1 in 25 live births for mothers above 45. Research shows that the extra chromosome is of maternal origin.

22. Three copies of chromosome 21 (21 trisomy)

23. Clinical features- Down’s Syndrome:

24. Teeth are pointed, cone shaped with gap.

25. The 5 A’s of Down Syndrome: Advanced Maternal Age Atresia (Duodenal) ASD Alzheimer Disease AML (<5 Y) /ALL (>5 Y)

26. Down’s syndrome is the most common inheritable cause of Mental Retardation

27. Cardiac disease: 50% of down syndrome patient have cardiac disease VSD-Ventricular septal defect ASD-Atrial septal defect AR-Atrial rugurgitation MR-Mitral rugurgitation Mitral valve collapse Cardiac problems are responsible for the majority of the deaths in infancy and early childhood.

28. Gastro-intestinal anomaly: Duodenal atresia Esophageal atresia Umbilical hernia Hirschsprung disease

29. Karyotype: Trisomy 21 type: 47,XX, +21(92%-94 %) for females ; 47 XY+21 for males Translocation type: 46,XX,der(14;21) (4% of cases). Mosaic type: having a mixture of cells with 46 and 47 chromosomes(1-4% of cases).

30. 1st trimester screening by measuring the nuchal thickness (by ultrasound that measures the thickness of the back of baby's neck ) with 92-93% sensitivity. Amniocentesis is done late (between 16-20 weeks of gestation) Chorionic-villous sampling ( CVS 10-12 weeks gestation) Diagnosis ( Screening )

31. Triple test is 70% sensitive . AFP HCG Estriol If inhibin A (high in DS) is added then ‘quadruple test’- sensitivity increase to 80%.

32. Common features : Congenital heart defects Renal Defects Mental Retardation Rocker Bottom feet Almost all affected babies die by the age of 1 Trisomy 13 & 18

33. Karyotypes : Trisomy 18 type: 47,XX, +18 Mosaic type: 46,XX/47,XX, +18 TRISOMY 18(Edward syndrome)

34. Trisomy 13( Patau syndrome)

35. Cytogenetic Disorders Involving Sex Chromosomes.

36. Genetic diseases associated with changes involving the sex chromosomes that can be either gain or loss of entire or parts of sex chromosomes. Most common chromosomal disorders are Turner syndrome and Klinefelter syndrome. Prevalence is approx 1 per 600 birth. Introduction:

37. Features of sex chromosomal disorder are: Delay in onset of puberty; Primary or secondary amenorrhea; Infertility; Ambiguous genitalia.

38. Monosomy of sex chromosome: ( Monosomy X: 45, X) i.e. only one X chromosome is present. Loss of one x chromosome in gametogenesis . Occurrence – 1 in 2500 live female births. Individuals are genetically female, not mature sexually and sterile. Turner syndrome:

39. Approximately 57% are missing an entire X chromosome, resulting in a 45,X. Of the remaining 43%, approximately one-third have structural abnormalities of the X chromosomes, and two-thirds are mosaics. Karyotyping:

40. Mosaic: The mosaic patients have a 45,X cell population along with normal cell types. e.g:45,X/46,XX.

41. Turner syndrome

42. Clinical Presentation: Patients generally present during infancy with edema of the dorsum of the hand and foot. As these infants develop, the swellings subside but often leave bilateral neck webbing and persistent looseness of skin on the back of the neck. Congenital heart disease is also common, affecting 25% to 50% of patients.

43. 50% of patients develop hypothyroidism. Presence of obesity, nonalcoholic fatty liver disease, and insulin resistance. The ovaries are atrophied.

44. At puberty there is failure to develop normal secondary sex characteristics. The genitalia remain infantile, breast development is inadequate, and there is little pubic hair. Shortness of stature (rarely exceeding 150 cm in height) and amenorrhea.

45. In approximately 80% of cases the X chromosome is maternal in origin, suggesting that there is an abnormality in paternal gametogenesis. The genes involved is the SHOX gene (short-stature  homeobox gene).

46. It is best defined as male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes. The incidence of this condition is reported to be approximately 1 in 660 live male births . Risk factor: Advanced maternal age (>40 years) is a risk factor. Klinefelter syndrome:

47. Karyotype: Classic Klinefelter syndrome is associated with a 47,XXY karyotype (90% of cases). This complement of chromosomes results from nondisjunction during the meiotic divisions in the germ cells

48. Clinical features: Increase in length between the soles and the pubic bone. Abnormally long legs; small atrophic testes often associated with a small penis. Lack of secondary male characteristics as deep voice, beard, and male distribution of pubic hair. Gynecomastia may be present

49. The cognitive abilities range from average to below average with modest deficit in verbal skills particularly those that are used in reading and language comprehension. Patients are at a higher risk for congenital heart disease. There is also an increased incidence of osteoporosis and fractures. Klinefelter syndrome is an important genetic cause of reduced spermatogenesis and male infertility.

50. There is increased incidence of type 2 diabetes. Patients are at a higher risk for congenital heart disease, such as mitral valve prolapse, atrial and ventricular septal defects. Patients have a 20- to 30-fold higher risk of developing germ cell tumors.

51. Hormone assay: Follicle-stimulating hormone (FSH), are consistently elevated, whereas testosterone levels are variably reduced. Estrogen levels are elevated.

52. Klinefelter’s Syndrome

53. Investigation : Karyotyping Imaging Amniocentesis Chorionic villi sampling Hormonal assay

54. Advanced technique: Karyotyping Fluorescence insitu hybridization(FISH) Polymerase chain reaction(PCR) Next generation sequencing(NGS).

55. When to do chromosomal test: High maternal age Abnormal ultrasound changes Abnormal AFP, B- hcg,estriol level Postnatal : Learning & developmental disability; growth retardation Infertility: Recurrent miscarriage, primary infertility

56. Classical Mendelian Inheritance Autosomal : Dominant Recessive Sex Chromosomal : X linked (Recessive/ Dominant ) Y linked Single Gene Disorders Non- Mendelian Inheritance Genomic Imprinting Mitochondrial Inheritance Trinucleotide Repeat Expansion Germline Mosaicism

57. Heterozygous state At least 1 parent affected Male-Female equally affected All generations affected Structural proteins are affected. Loss of function> Gain of function mutation Autosomal Dominant Disorders

58. Affects Enzymatic proteins ( Inborn errors of metabolism) Homozygous state Generation skips Male Female equally affected Autosomal Recessive Disorders

59. Father to son transmission is Zero. Most common sex linked pattern of Inheritance X linked genes – encode enzyme genes More common in males X linked Recessive Disorders

60. Genomic Imprinting: Prader Willi Syndrome ( Maternal Imprinted, Paternal deleted or mutated) Presents with Mental Retardation, Obesity, Hypotonia , Hypogonadism Angelman Syndrome ( Paternal Imprinting, Maternal Deleted mutated) Are Happy puppets presents with Seizures, Ataxia, Mental Retardation, Inappropriate Laughter. Chromosome Involved : Chromosome 15 Non- Mendelian Inheritance Disorders

61. Long nucleotide repeats Causes Neurodegenerative diseases Huntington’s Disease : CAG repeats Fragile X Syndrome : GAA repeats Myotonic Dystrophy: CTG repeats Trinucleotide Repeat Mutations

62. Second most common cause of Mental Retardaion Large face Large mandible Large Testis ( Macro- orchidism ) Large everted Ears

63. Genetics Genetic Disorders Karyotyping FISH Turner vs Klinefelter Down vs Edward vs Patau AD vs AR vs XLR Quick Review

64. THANK YOU