16_GENETICS by prof. Adeniji of gene.pptx

Genetics of numerical and structural disorder

1. GENETICS I INTRODUCTION TO DEVELOPMENTAL PATHOLOGY Certain disorders in human are inherited or related to disturbances in intrauterine development. Not all congenital disorders are hereditary and not all hereditary disorders manifest at birth, Not all genetic disorders are hereditary (room for new mutations).

2. Magnitude of the problem Worldwide, at least 1 in 50 newborns has a major congenital anomaly, 1 in 100 has a single gene abnormality, and 1 in 200 has a major chromosomal abnormality. About 70% of all birth defects resulted from unknown causes. About 20% due to hereditary diseases.

3. About 4% due to cytogenetic diseases About 2% due to drugs, chemicals, irradiation. About 2% due to maternal infection About 1% due to maternal metabolic factors About 1% due to birth trauma and uterine factors.

4. Although about 4% of birth defects are due to xsomal abnormalities, cytogenetic analysis of fetuses spontaneously aborted early in pregnancy show that up to 50% have chromosomal abnormalities.

5. Incidence of specific numerical chromosomal abnormalities is abortuses is several times higher than in term infants, indicating that most such chromosomal defects are lethal.

6. In developed countries, developmental and genetic birth defects account for ½ of the deaths in infancy and childhood. In developing countries, however, 95% of infant mortality result from infectious diseases and malnutrition

7. This does not mean there are more developmental and genetic birth defects in developed than in developing countries. Reduction in the incidence of birth anomalities can be achieved by the following: i . Genetic counselling

8. ii. Early prenatal diagnosis iii. Identification of high-risk pregnancies iv. Avoidance of possible exogenous teratogens. v. Prenatal dietary folic acid supplements – this has reduced the incidence of congenital neural tube defects.

9. Principles of Teratology Teratology is the study of developmental anomalies (Greek teraton , monster). Teratogens are chemical, physical and biological agents that cause developmental anomalies.

10. Principles of Teratology Contd. Although there are few proven teratogens in humans, but many drugs and chemicals are teratogenic in animals and are potentially dangerous for humans. Malformation are morphologic defects or abnormalities of an organ, part of

11. Principles of Teratology Contd. Malformation are morphologic defects or abnormalities of an organ, part of an organ, or anatomical region due to perturbed morphogenesis. Exposure to a teratogen may result in a malformation but this is not invariably the case. Why?

12. Principles of Teratology Contd. General principles of teratology include: i . Susceptibility to teratogens is variable: This is due to the variability of the genotypes of the fetus and the mother. (Genotype as in genetic make up) e.g. In fetal alcohol syndrome, which affects some children of alcoholic mothers.

13. Principles of Teratology Contd. General principles of teratology include: ii. Susceptibility to teratogens is specific for each embryologic stage – means teratogens are teratogenic only at particular times of development – time of exposure during development.

14. Principles of Teratology Contd. Periods of maximal sensitivity to tetratogens vary for different organ systems but are limited to the first 8 weeks of pregnancy . E.g. CNS – 2 nd to 5 th week Heart – 3 rd to 6 th week Extremities – About 4 th to 7 th week Eyes- About 4 th to 8 th week External genitalia- About 6 th to 8 th week

15. Principles of Teratology Contd. iii. The mechanism of teratogenicity is specific for each teratogen. Many drugs and viruses affect specific tissues ( e,g , neurotropism and cardiotropism ) and so damage some developing organs more than others.

16. Principles of Teratology Contd. iv. Teratogenesis is dose-dependent – this means that each teratogen has a safe dose below which no teratogenesis occurs, however, since no absolute safe dose can be predicted for every woman, teratogens should be avoided during pregnancy.

17. Principles of Teratology Contd. v. Teratogens produce death, growth retardation, malformation or functional impairment. The outcome of exposure depends on the interaction between the teratogenic influences, the maternal organism, and the fetal -placental unit.

18. Principles of Teratology Contd. Proven teratogens include most cytotoxic drugs, alcohol, some antiepileptic drugs, heavy metals, thalidomide e.t.c.

19. Errors of Morphogenesis Normal intrauterine and postnatal development depends on sequential activation and repression of genes. A fertilized ovum (zygote) has all the genes of an adult organism, but most of them are inactive.

20. Errors of Morphogenesis Contd. The most common consequence of toxic exposure at the preimplantation stage is death of the embryo, which often passes unnoticed (not malformations.

21. Errors of Morphogenesis Contd. Injury during the 1 st 8-10 days after fertilization usually causes incomplete separation of blastomeres , which lead to conjoined (twins that are joined) e.g. At the head ( craniopagus ), thorax ( thoracopagus ), rump ( ischiopagus ).

22. Errors of Morphogenesis Contd. Most complex developmental abnormalities affecting several organ systems are due to injuries that occur between implantation of the blastocyst and early organogenesis. Formation of primordial organ systems is the stage of embryonic development most susceptible to teratogenesis .

23. Errors of Morphogenesis Contd. Disorganized or disrupted morphogenesis may have minor or major consequences at the level of cells and tissues; organs or organ system; and anatomical regions.

24. Defination of terms: Agenesis – Complete absence of an organ primordium e.g. Total lack of an organ, as in renal agenesis absence of part of an organ, agenesis of corpus callosum . Aplasia – Persistence of an organ anlage or rudiment without the mature organ e.g. Pulmonary aplasia .

25. Defination of terms: Contd iii. Hypoplasia – Reduced size due to incomplete development of all or part of an organ e.g. microcephaly . iv. Dysraphic anomalies – defects caused by failure of apposed structures to fuse.

26. Defination of terms: Contd v. Involution failure- Persistence of embryonic or fetal structure that should have involuted at certain stages of development e.g. Persistent thyroglossal duct. vi. Division failures – Incomplete cleavage of embryonic tissues e.g. syndactyl .

27. Defination of terms: Contd vii. Atresia – Incomplete formation of a lumen. E.g. Esophageal atresia viii. Ectopia or heterotopia – When an organ is situated outside its normal anatomic site. ix.Dystropia –Inadequate migration of an organ that remains where it was during development e.g. Pelvic kidney, cryptorchidism .

28. Mechanism of Developmental Defects They include: i . Polytopic effect – This occurs when a noxious stimulus affects several organs that arte simultaneously in critical stages of development.

29. Mechanism of Developmental Defects ( Contd ) ii. Monotopic effect – This refers to a single localized anomaly that results in a cascade of pathogenetic events. iii. Developmental sequence anomaly – This is a pattern of defects related to a single anomaly or pathogenic mechanism. E.g. Potter complex, pulmonary hypoplasia , signs of intrauterune fetal compression, oligohydramnios .

30. Mechanism of Developmental Defects ( Contd ) iv. Developmental syndrome – this refers to multiple anomalies that are pathogenetically related e.g. Polytopic effect during a critical developmental period. Many developmental syndromes are due to xsomal or single gene defects.

31. Mechanism of Developmental Defects ( Contd ) v. Developmental association ( Syntropy ) - This refers to multiple anomalies that are associated statistically but do not necessarily share the same pathogenetic mechanisms.

32. Deformation This is defined as an abnormality of form, shape or position of a part of the body that is caused by mechanical forces. These forces may be external (e.g. Amniotic bands in the uterus) or intrinsic (e.g. Fetal hypomobility caused by CNS injury).

33. GENETICS II INTRODUCTION TO GENETICS Genetics is the study of inheritance in all of its manifestations, from the distribution of human traits in a family pedigree to the biochemistry of the genetic material in our chromosomes.

34. Genetics is concerned with the transmission, expression, and evolution of genes, the molecules that control the function, development, and ultimate appearance of individuals. There are 3 general areas of genetics: Classical genetics Molecular genetics Evolutionary genetics

35. Classical genetics – This is concerned with the xsomal theory of inheritance , i.e. the concept that genes are located in a linear fashion in xsomes and that the relative positions of genes can be determined by their frequency in offspring .

36. Molecular genetics - This is the study of the genetic material: its structure, replication, and expression; as well as recombinant DNA techniques (in genetic engineering, including human genome project).

37. Evolutionary genetics – This is the study of the mechanisms of evolutionary change, or changes in gene frequencies in populations.

38. Structure of Xsome Organisms are classified into eukaryotes and prokaryotes. Eukaryotes have true membrane-bound nuclei, while prokaryotes lack true nuclei (e.g. Include bacteria and blue-green algae ). Nucleus is made up of: i . DNA ( less than 20% of the mass)

39. ii. Proteins called nucleoprotein – these include histone protein (this binds to the DNA and control its coiling) and non-histone proteins (these a re enzymes for DNA and RNA synthesis, and regulatory proteins). iii. RNA

40. Xsomes are DNA complexed with histone protein . Xsomes were discovered in 1842 by C. Von Nageli , but the term was coined by w. Waldeyer in 1888 – it means ‘ colored body’. Xsomes are classified according to their length and positions of their constrictions or centromeres .

41. Centromere is the point at which the 2 identical strands of xsomal DNA, called sister chromatids , attached to each 0ther during mitosis. Metacentric Xsomes – 1, 3, 19, 20. The centromere is exactly in the middle.

42. ii. Submetacentric Xsomes – 2, 3-12, 16-18, and X. The centromere divides the xsome into a short arm (p, from French, petit) and a long arm (q, next letter). iii. Acrocentric Xsomes – 13, 14, 15 , 21, 22, Y . The centromere is eccentrically located.

43. Stains are also used to classify xsomes into seven groups A to G. Group A – 1-3 Group B – 4 & 5 Group C – 6-12 Group D – 13-15 Group E -16-18 Group F – 19 & 20 Group G -21 & 22 Then X and Y

44. Xsomes are broadly classified into autosomes and sex xsomes ; X and Y. The total Xsomal complement of a cell is referred to as Karyotype . Most higher eukaryotic cells are diploid, i.e. The xsomes occur in pairs. One member of each pair came from each parent. Haploid cells (gametes) have only one copy of each xsome.

45. Therefore, total xsomal complement of a diploid cell is 46, 23 pairs of 22 autosomes and 1 pair of XX and XY depending on the sex of the individual. Thus, male is written as 46XY and female written as 46XX. An ovum will always be 23X, while a spermatozoa may be 23X or 23Y .

46. Homologous xsomes referred to members of the same pair. This applies to xsome 1 to 22, and XX in female . XY pair is referred to as heterologous xsomes.

47. Structure of DNA The structure of DNA was deduced by James Watson and Francis Crick in 1953. It is a double-stranded molecule shape like a twisted ladder. The backbones of the helices are repeating units of Sugars ( deoxyribose ) and phosphate groups. The rungs of the ladder are base pairs, with one base extending from each back bone.

48. Structure of DNA ( Contd ) Only four bases normally occur in DNA i.e. Adenine, thymine, gaunine , and cytosine (ATGC). Note that there is no restriction on the order of bases on one strand . However, complementarity exists between bases forming a rung. If one base of the pair is adenine, the other must be thymine; if one base is guanine, the other must be cytosine. *( Adenine and guanine are purine bases while thymine and cytosine are pyrimidine bases ).

49. Genes Genes are specific segments of DNA that encode particular proteins e.g. Structural proteins, receptors, enzymatic proteins and regulatory proteins. Human genome contains about 3.2 billion DNA base pairs. However, genome contains only 20,000 protein-encoding genes (about 1.5% of the genome). Bulk of the noncoding region of the DNA binds proteins, and regulate gene expression.

50. Genes Regions of the DNA: Protein coding sequences (the exons) - T hese refer to segments of DNA within genes that are transcribed and translated. Non-protein coding sequences: These include; Promoters and enhancer regions – regions of the DNA that allow RNA polymerase to attach and begin transcription.

51. Non-coding regions contd Binding sites for factors that organize and maintain higher order chromatin structures. Noncoding regulatory RNA (introns) – these are segments of DNA (about 60% of the genome) that are transcribed into RNA but never translated into protein sequences . Mobile genetic elements (transposons) - About 1/3 of human genome. Special structural regions (telomeres and centromeres)

52. Structure of RNA This is a single stranded nuclei acid that contains ribose sugar instead of deoxyribose sugar in DNA. It contains 2 purine bases – Adenine and guanine and 2 pyrimidine bases – cytosine and uracil (in contrast to DNA that has thymine instead of uracil ).

53. Structure of RNA ( Contd ) There are 3 types of RN A: i . Messenger RNA- this is transcribed from DNA with enzyme RNA polymerase. ii. Transfer RNA which brings amino acids into the ribosome. iii. Ribosomal RNA

54. Codons Three nucleotide bases form a codon that specifies one of the twenty naturally occuring aminoacids used in protein synthesis. Several codons may code for the same amino acid e.g. CUU, CUA, CUG all code for leucine .

55. Stop codons are where termination of translation of protein synthesis occur e.g. UAA, UAG, UGA – RNA ATT, ATC, ACT – DNA Start codon is usually where translation begins – AUG that code for methionine . Other examples GUU, GUC, GUA, GUG – Valine CAA, GAG – Glutamine

56. Mutations A mutation is a stable heritable change in DNA. It is a permanent change in the DNA Consequences of mutations are highly variable: Some have no functional consequence.

57. Mutations ii. Others are lethal and cannot be transmitted iii. In between, is a broad range of mutations that account for genetic polymorphisms of any species. * Note – that evolution is based on the occurrence over time of non lethal mutations that alter the ability of a species to adapt to its environment.

58. Types of Mutations 1. Point mutations within coding sequences: This is replacement of one base by another. If this involves coding region of a gene, there are 3 possible consequences. a. Conservative missense (Synonymous) mutation - new codon codes for biochemically similar amino acid without change in the function of the protein. CGA and CGC both code for arginine.

59. Types of Mutations ( contd ) b. Nonconservative missense mutation (75%) - new codon codes for a different amino acid. E.g. An adenine replacing thymine in the beta-globin gene replaces glutamic acid (CTC) with valine (CAC). c. Nonsense mutation (4%) – base substitution results in stop codon. E.g. a point mutation in a beta-globin gene affecting the codon for glutamin (GTC) creates a stop codon (ATC) if G is substituted for A . This is seen in beta-thalassemia.

60. Types of Mutations ( contd ) 2. Mutations within noncoding sequences: Mutations involving promoter and enhancer sequences will affect transcription of DNA. Mutations affecting introns may result in abnormal mRNA processing. 3. Frameshift mutations: insertion or deletion of bases that is not a multiple of 3 results in alteration of the reading frame.

61. Types of Mutations ( contd ) 4. Large deletions : a large segment of the DNA is deleted, and the entire coding region of a gene may be removed resulting in the absence of protein product. It may also result in fusion of coding regions of nearby genes with formation of a fused gene and a hybrid protein .

62. Types of Mutations ( contd ) 5. Trinucleotide-repeat mutation: This is characterized by expansion of repeat seqence of three nucleotides. e.g. In Huntington disease, fragile X syndrome, myotonic dystrophy, Friedreich ataxia . In fragile X syndrome, there are about 250 to 4000 repeats of CGG sequence in familial mental retardation 1, FMR1 gene (average of 29 repeats in normal individual). The expansion prevents normal expression of FMR1 gene, resulting in mental retardation.

63. Consequences of Mutations This may lead to formation of an abnormal protein or reduction in output of the gene product. Any type of protein may be affected; enzymes, membrane receptors and transport systems, structural proteins (structure, function, and quantity), proteins in signal transductions, etc Pattern of inheritance is mostly related to the kind of protein affected by the mutation.

64. Consequences of enzyme defects A → B → C → D Initial substrate Intermediate end products A single gene defect can have 4 consequences: 1 – Failure to complete a metabolic pathway with decreased amount of end product: e.g. Albinism – deficiency of tyrosinase enzyme for biosynthesis of melanin from tyrosine .

65. Consequences of enzyme deficiency ( contd ) 2. Accumulation of unmetabolized substrate: e.g. Phenylketonuria – deficiency of phenylalanine hydroxylase will lead to accumulation of phenylalanine.

66. Consequences of enzyme deficiency ( contd ) 3. Storage of an intermediary metabolite: e.g. Glycogen storage disease that results from a deficiency of glucose-6-phosphatase that will convert glucose-6-phosphate into glucose will lead to its alternative conversion to glycogen.

67. Consequences of enzyme deficiency ( contd ) 4. Failure to inactivate a tissue-damaging substrate. Example is alpha-1 antitrypsin deficiency, being unable to inactivate neutrophil elastase in the lungs (resulting in destruction of elastin in the walls of lung alveoli, causing emphysema).

68. Consequences of defects in receptors and transport systems Examples: Familial hypercholesterolemia – reduced synthesis or function of LDL receptors. Cystic fibrosis – defective transport system for chloride ions in exocrine glands, sweat ducts, lungs, pancreas, etc.

69. Consequences of alterations in structure, function, or quantity of nonenzymatic proteins Examples: Hemoglobinopathies – e.g., Sickle cell disease. Thalassemias . Hereditary spherocytosis. Muscular dystrophies.

70. Disorders associated with structural proteins Examples: Marfan syndrome – This is a connective tissue disorder with manifestations in the skeleton, eyes, and cardiovascular systems. It results from inherited defect in extracellular glycoprotein, fibrillin-1. Ehlers- Danlos syndromes – results from defect in the synthesis or structure of fibrillar collagen .

71. GENETICS III CHROMOSAL DISORDERS Cytogenetics is the study of xsomes and their abnormalities in cells. Chromosal abnormalities can either be structural or numerical.

72. Structural Xsomal Disorders These result from breaks in chromosome , usually due to ionizing radiation, physical stress, or chemical compounds. Single breaks will result in formation of 2 fragments: accentric fragment and centric fragment . This can result in restitution or deletion.

73. Two breaks in the same xsome can result in deletion and inversion. Two breaks involving nonhomologous chromosomes can result in translocation.

74. Examples of Structural Xsomal Abnormalities 1. Xsomal deletions – A deletion is loss of a portion of a xsome and involves either a terminal or middle segment. e.g., a. Cri du chat syndrome – deletion in short arm of xsome 5.

75. Examples of Structural Xsomal Abnormalities ( Contd ) b. Familial retinoblastomas – deletions involving the long arm of xsome 13. c. Wilm tumor aniridia syndrome – deletion in the short arm of xsome 11.

76. Examples of Structural Xsomal Abnormalities ( Contd ) 2. Xsomal inversions: This refers to a process in which a xsome breaks at two points, the affected segment inverts and then reattaches. There are 2 types of inversions i . Pericentric inversion- results from breaks on opposite sides of the centromere .

77. Examples of Structural Xsomal Abnormalities ( Contd ) ii. Paracentric inversion- involves breaks on the same arm of the xsome. ** Inversions are usually associated insignificant or no consequences . 3. Translocations: refers to exchange of genetic material between two non-homologous xsomes.

78. Examples of Structural Xsomal Abnormalities ( Contd ) There are 2 types of xsomal translocations: i . Reciprocal translocation: This refers to exchange of accentric xsomal segments between different ( nonhomologous ) xsomes. A reciprocal transloction is balanced if there is no loss of genetic material.

79. Examples of Structural Xsomal Abnormalities ( Contd ) Consequences of reciprocal translocation: a. Formation of a fusion gene- e.g., t9,22 in CML b. Overexpression of some genes especially if they are removed from their control e.g. T8, 22 in Burkitt . c. Partial trisomy e.g. Translocation form of Down syndrome.

80. Examples of Structural Xsomal Abnormalities ( Contd ) Consequences of reciprocal translocation: d. Partial monosomy e.g. e. Mosaicism . ii. Robertsonian translocations: This involves the centric segments of acrocentric xsomes (13-15, 21, 22, Y) resulting in the formation of one large metacentric xsome and small xsomal fragment.

81. Examples of Structural Xsomal Abnormalities ( Contd ) The fragment that lacks centromere is lost during subsequent divisions . It can also be balanced if there is no loss of genetic material. The carrier of Robertsonian translocations is usually phenotypically normal , but may be infertile. If they are fertile, their offsprings may have congenital malformations.

82. Examples of Structural Xsomal Abnormalities ( Contd ) 4. Ring Xsomes: These are formed by a break involving both telomeric ends of a xsome, deletion of the accentric fragments and end-to-end fusion of the remaining centric portion of the xsome. Consequences depend on the amount of genetic material lost because of the break. They include: i . No consequences ii. It may impede normal meiotic division.

83. Examples of Structural Xsomal Abnormalities ( Contd ) 5. Isochromosomes : This results from faulty centromere division giving rise to one pair corresponding to the short arms attached to the upper portion of the centromere and the other to the long arms attached to the lower segment. E.g., a variant of Turner syndrome ( about 15% of Turners) with isochromosome of the X xsome.

84. Examples of Structural Xsomal Abnormalities ( Contd ) A woman with a normal X xsome and an isochromosome composed of long arms of the X xsome is monosonic for all genes on the missing short arm and this accounts for the abnormal development in these persons.

85. CHROMOSAL DISORDERS Numerical Xsomal Disorders These result mainly from nondisjunction . Nondisjunction is a failure of paired chromosomes or xmatids to separate and move to opposite poles of the spindle at anaphase during mitosis or meiosis.

86. CHROMOSAL DISORDERS Numerical Xsomal Disorders Nondisjunction leads to aneuploidy if only one pair of xsomes fails to separate, or polypoid if the entire set does not divide and all the xsomes are segregated into a single daughter cell.

87. CHROMOSAL DISORDERS Numerical Xsomal Disorders Aneuploidy 2 to nondisjunction in somatic cells leads to trisomy (2n+1) in one daughter cell, and monosomy (2n-1) in the other daughter cell. In germ cells, one has 2 copies of the same xsome (n+1 and the other lacks the affected xsome (n-1)

88. CHROMOSAL DISORDERS Numerical Xsomal Disorders Anaphase lag is a special form on nondisjunction in which a single xsome or xmatid fails to pair with its homologue during anaphase. The xsome is therefore not incorporated into the nucleus of the daughter cells. The consequence is one daughter cell being monosonic for the missing xsome, and the other remains euploid .

89. CHROMOSAL DISORDERS Definition of terms Haploid – A single set of each xsome (23 in humans). *Only germ cells are haploid. Diploid- A double set (2n) of each xsome (46 in humans) most somatic cells are diploid. Euploid –Any multiple (from n to 8n) of the haploid number of xsomes. Multiple greater than 2 (diploid) is polypoid, e.g., triploid, tetraploid etc.

90. CHROMOSAL DISORDERS Definition of terms( Contd ) Aneuploid – Karyotypes that are not exact multiples of the haploid number. E.g., many cancer cells are aneuploid . Monosomy – The absence of one xsome of the homologous pair in a somatic cell. E.g., Turner syndrome with a single X xsome. Trisomy - The presence of an extra copy of a normally paired xsome e.g. Down syndrome with 3 xsome.

91. CHROMOSAL DISORDERS Definition of terms( Contd ) Mosaicism – When the body contains two or more karyotypically different cell lines. May involve autosomes or sex xsomes .

92. CHROMOSAL DISORDERS Pathogenesis of Numerical disorders Causes are unknown, but possible factors include radiations, viruses and chemicals. These agents affect the mitotic spindle or DNA synthesis in experimental animals.

93. CHROMOSAL DISORDERS Pathogenesis of Numerical disorders However, 2 important factors in the genesis of numerical aberrations are: i . Non disjunction during meiosis – this is more common in persons with structurally abnormal xsomes. ii. Maternal age – Especially >40years. The older the increase in the probability.

94. CHROMOSAL DISORDERS Numerical Xsomal disorders at various stages of pregnancy Aberrations seen at birth differ from those seen in early spontaneous abortuses . About 0.3% of all live born infants have a xsomal abnormality . The most common xsomal abnormalities at birth are trisomies 21(most frequent), 18, 13, trisomies involving X or Y xsomes (47, XXX; 47, XXY; 47, XYY).

95. CHROMOSAL DISORDERS Numerical Xsomal disorders at various stages of pregnancy Trisomy 16 is nearly always lethal in utero , very few fetuses with 45,X survive to term, fetus with trisomy 21 has a better chance of surviving to birth.

96. CHROMOSAL DISORDERS Numerical Xsomal disorders at various stages of pregnancy People with trisomy 21 may survive for years, while trisomy of the X xsome may only result in abnormal development but not lethal. Note – that absence of an X-xsome in 45, Y will invariably lead to early abortion.

97. CHROMOSAL DISORDERS Examples of Trisomies 1. Trisomy 21 (Down syndrome) This is the most common cause of mental retardation . Live born infants are only a fraction of all conceptuses with this defect because about 2/3 abort spontaneously or die in utero .

98. CHROMOSAL DISORDERS Pathogenesis Trisomy 21 can result from 3 mechanisms: i . Nondisjunction in the first meiotic division (about 95%): the extra xsome 21 is of maternal origin in 95% of Down syndrome children. ii. Translocation of an extra long arm of xsome 21 to another acrocentric xsome (about 5%).

99. CHROMOSAL DISORDERS Pathogenesis ii. Mosiacism for trisomy 21: this is caused by nondisjunction during mitosis of a somatic cell early in embryogenesis accounts for about 2% of Down syndrome .

100. CHROMOSAL DISORDERS Epidemiology The incidence of trisomy 21 correlates strongly with increasing maternal age. Up to mid-30s – risk is 1 per 1000 liveborn at age 45 year – 1 in 30 The risk of a mother having a second child with Down syndrome is 1% regardless of maternal age, unless the syndrome is xsome 21 translocation.

101. CHROMOSAL DISORDERS Morphology/ Clincal Features Persons with Down syndrome have xtic appearance even at birth, and the diagnosis can be confirmed by cytogenetic analysis . Mental status: They are ususlly mentally retarded. The Iqs decline progressively with age.

102. CHROMOSAL DISORDERS Morphology/ Clincal Features Craniofacial features: ( i )Flat face and occiput , (ii) low-bridged nose, (iii) reduced interpapillary distance, (iv) epicanthal folds etc. Heart: 1/3 of them have cardiac malformations. They include: ( i ) A-V anomaly, (ii) VSD, (iii) ASD, (iv) TOF (v) PDA Skeleton: Shorter bones of the ribs, pelvis and extremities; simian crease in the palm; etc.

103. CHROMOSAL DISORDERS Morphology/ Clincal Features GIT: Duodenal stenosis or atresia , imperforate anus, Hirschsprung dx . Reproductive system : Men are usually sterile due to arrested spermatogenesis. Few women have given birth, bout 40% of their children had trisomy 21. Hematologic disorders: increased risk of developing leukemia at all ages. <3 years – more of acute non lymphoblastic leukemia <3 years- most are acute lymphoblastic

104. CHROMOSAL DISORDERS Morphology/ Clincal Features Neurologic disorders: Alzheimer disease which is usually demonstrable by age 35. Life expectancy: survival during 1 st decade depends on absence or presence of congenital heart disease. When there is no heart disease, only about 5% die before age 10. Only 10% reach age 70.

105. CHROMOSAL DISORDERS Morphology/ Clincal Features 2. Trisomy 18 (Edward syndrome) Incidence: 1 in 10,000 live births. Most affected individuals are female, with 80 to 90% mortality by 2 years of age. Features Small nose, small mouth with receding lower jaw, abnormal ears; lack of distal flexion creases on the fingers Severe mental retardation

106. CHROMOSAL DISORDERS Morphology/ Clincal Features 2. Trisomy 13 ( Patau Syndrome) Incidence: 1 in 20,000 live births. age. Features Cleft palate, cleft lip, congenital heart defect, polydactyl. Severe mental retardation. Most die in the first year of life .

107. CHROMOSAL DISORDERS Numerical aberrations of sex chromosomes Additonal sex xsomes produce less severe clinical manifestations than extra autosomes , and are less likely to disturb critical stages of development. The phenotype is less severely affected with additional X xsome as a result of lyonization effect.

108. CHROMOSAL DISORDERS Numerical aberrations of sex chromosomes( Contd ) Note that males carry only one X xsome but the same amounts of X xsome gene products as female because of he lyon effect : this is explained as thus: i . In females, one X xsome is irreversibly inactivated early in embryogenesis. This is detectable in interphase nuclei as heterochromatic clump of xmatin attached to the inner nuclear membrane, called Barr body.

109. CHROMOSAL DISORDERS Numerical aberrations of sex chromosomes( Contd ) ii. Either the paternal or maternal X xsome is inactivated randomly. iii. Inactivation of the X xsome is permanent and transmitted to progeny cells i.e. Paternally or maternally derived X xsomes are propagated clonally. All females are therefore mosaic for paternally or maternally derived X-xsomes.

110. CHROMOSAL DISORDERS Concept of pseudoautosomal region This explains the fact that part of the inactivated X-xsome is still functional. If not, all individuals with 45X, and others with extra X-xsomes are suppose to be phenotypically normal. A part of the short arm of the X-chromosomes is known to escape inactivation, and this region, which can pair with a homologous region on the short arm of the Y chromosome is known as pseudoautosomal region .

111. CHROMOSAL DISORDERS Concept of pseudoautosomal region( Contd ) Therefore, genes in this location are present in 2 functional copies in both males and females; and Turners are haplo insufficient for these genes while patients with more than 2 X xsomes have more than 2 functional copies. Example of a gene in this region is SHOX, which is associated with height , and haplo insufficient in Turners may explain the short stature of Turner.

112. CHROMOSAL DISORDERS Y Chromosome Genes on the Y xsome are the key determinants of gender phenotype . This testis-determining gene (SRY, Sex-determining region, Y) is located near the end of the short arm of y chromosome. Mutations in this gene leads top XY females, while translocations that introduce this gene into an X-xsome produce XX males

113. CHROMOSAL DISORDERS 1. Turner syndrome, 45,X This refers to the spectrum of abnormalities that results from complete or partial X-xsome monosomy in a phenotypic female. Incidence – About 1 in 5,000 to 1 in 10,000 live born female infants. In ¾ of cases, the single X xsome of Turner is of maternal origin . The incidence does not correlate with maternal age, and the risk in subsequent female infant is not increased. It is one of the most common aneuploidy in human conceptuses but almost all are aborted spontaneously.

114. CHROMOSAL DISORDERS Types of Turners i . Monosomy X : About 50% of women with Turners lack an entire X-xsome. ii. Mosaic: e.g., with 45,X/46,XX karyotype (15% of Turners). They tend to milder phenotypic manifestation and may be fertile. In about 5% of patients, the mosaic karyotype is 45,X/46,XY. These patients have abnormal gonads that should be removed prophylactically because they are at 20% risk of developing germ cell cancer

115. CHROMOSAL DISORDERS Types of Turners ( Contd ) iii. Other aberrations include isochromosome of the long arm, translocations, and deletions.

116. CHROMOSAL DISORDERS Clinical features of Turners Primary amenorrhea and sterility Short stature- almost all are less than 5 feet Short webbed neck, low posterior hairline, wide carrying angle of the arms( cubitus valgus ), broad chest with widely spaced nipples, hyperconvex fingernails. Small mandible, prominent ears, and epicanthal folds.

117. CHROMOSAL DISORDERS Clinical features of Turners ( Contd ) Defective hearing and vision About 20% are mentally defective Greater risk for xnic autoimmune thyroiditis and goitre. CVS anomalies occur in about 50% of Turners e.g. Coarctation of the aorta- 15% of Turners Bicuspid aortic valve- about 1/3 Essential hypertension in some Dissecting aneurysm-occasionally cause of death

118. CHROMOSAL DISORDERS Clinical features of Turners ( Contd ) Ovaries – they lose oocytes rapidly and none may remain by 2 years of age (undergone menopause long before reaching menarche). **Children with Turner when treated with growth hormone and estrogens have excellent prognosis and a normal left except infertility.

119. CHROMOSAL DISORDERS 2. Klinefelter Syndrome, 47, XXY Also called testicular dysgenesis . It is prominent cause of male hypogonadism and infertility. Incidence – About 1 in 1000 male newborns. ½ of all XXY conceptises are lost due to spontaneous abortion. In about 50%, extra X-xsome in paternal .

120. CHROMOSAL DISORDERS Types of Klinefelter i . 47, XXY karyotype – 80% ii. Mosaics: e.g. 46Xy / 47XXY More than 2 X-xsomes – e.g., 48,XXXY. Note: that additional X-xsomes correlate with a more abnormal phenotype

121. CHROMOSAL DISORDERS Clinical Features Manifestation during childhood are behavioral and psychiatric. Average 10 is somewhat reduced. Children tend to be tall and thin with relatively long legs. Small testes and penis. Feminine xtics e.g. High pitched voice, gynecomastia , and female pubic hair distribution.

122. CHROMOSAL DISORDERS Clinical Features ( Contd ) Azoospermia ** Treatment with testosterome will virilize them but does not restore fertility.

123. CHROMOSAL DISORDERS 3. XYY male Incidence – 1 in 1000 male newborns Features -Tall stature, development of cystic acne Aggressive antisocial behavior

124. CHROMOSAL DISORDERS 4. Females with Multiple X xsomes 47, XXX – Most of normal intelligence, they may have some difficulty in speech, learning, and emotional responses. They are usually fertile. Women with 4 and 5 X xsomes are also reported. They superficially resemble women with Down syndrome and they do not mature sexually.

125. CHROMOSAL DISORDERS HERMAPHRODITISM AND PSEUDOHERMAPHROTIDISM Sex of an individual can be defined on several grounds: Genetic sex Gonadal sex Ductal sex ( Mullerian vs Wolffian ducts) Phenotypic or genital sex True hermaphrodite possesses both ovary and testicular tissue , separate sides or together same side.

126. CHROMOSAL DISORDERS HERMAPHRODITISM AND PSEUDOHERMAPHROTIDISM Pseudohermaphrodite implies a disagreement between phenotypic and gonadal sex. Female pseudohermaphrodite has ovaries and but male external genitalia. Male pseudohermaphrodite has testes but female-type genitalia. The karyotype of true hermaphrodite is 46,XX in 50% of cases. The remaining are usually mosaics (46,XX/46,XY)

127. CHROMOSAL DISORDERS Diagnosis of additional X xsomes Buccal smear to ascertain the presence of a Barr body in a male. Women with supernumeracy X xsomes have additional Barr bodies. Confirmation is by karyotyping .

128. GENETICS IV SINGLE GENE DISORDERS These are also called Mendelian disorders, and they follow the classic laws of mendelian inheritance, which are: i . A mendelian trait is determined by 2 copies of the same gene called alleles, located at the same locus on 2 homologous xsomes. In the case of the X and Y xsomes in male, a trait is determined by just one allele .

129. GENETICS IV SINGLE GENE DISORDERS ii. Autosomal genes are those located on one of the 22 autosomes . iii. Sex-linked traits are encoded by loci on the X xsome iv. A dominant phenotypic trait requires the presence of only one allele of a homologous gene pair i.e. The dominant phenotype is present whether the allelic genes are homozygous or heterozygous.

130. GENETICS IV SINGLE GENE DISORDERS v. A recessive phenotypic trait demands that both alleles be identical, that is homozygous. vi. Codominance is a situation in which both alleles in a heterozygous gene pair are fully expressed (e.g., the AB blood group gene)

131. GENETICS IV SINGLE GENE DISORDERS A single mutant gene may lead to many end effects, termed pleotrophism , and mutations at several genetic loci may produce the same trait (genetic heterogeneity) e.g., pleotrophism is sickle cell anemia. Genetic heterogeneity- childhood deafness resulting from any of 16 different types of autosomal recessive mutations.

132. GENETICS IV Classification of single gene disorders i . Autosomal dominant ii. Autosomal recessive iii. Sex-linked dominant iv. Sex-linked recessive

133. GENETICS IV Classification of single gene disorders Autosomal dominant disorders Features: i . Males and females are equally affected. ii. The trait encoded by the mutant gene can be transmitted to succesive generations (unless the dx interferes with reproductive capacity).

134. GENETICS IV Classification of single gene disorders Autosomal dominant disorders Features: iii. Unaffected members of a family do not transmit the trait to their offspring. iv. Except in a new mutation, everyone with the disease has an affected parent.

135. GENETICS IV Classification of single gene disorders Autosomal dominant disorders Features: v. The proportions of normal and diseased offspring of patients with the disorder are on average speed. vi. Clinical features can be modified by reduced penetrance and variable expressivity:

136. GENETICS IV Classification of single gene disorders Autosomal dominant disorders Features: Penetrance is the percentage of individuals that posses the mutant and express the disease. E.g., 50% penetrance means 50% of those who carry the gene express the trait.

137. GENETICS IV Classification of single gene disorders Autosomal dominant disorders Features: Variable expressivity means different expression of the trait by individuals carrying the same abnormal gene. In many conditions, the age at onset is delayed i.e. Symptoms and signs do not appear until adulthood

138. GENETICS IV Classification of single gene disorders Autosomal dominant disorders Pathogenesis of AD diseases Two types of mutations and two categories of proteins are involved: Loss of function mutations(more common)- Those usually affect regulatory proteins and subunits of large structural proteins. Gains of function mutations(less common)- These endow normal proteins with toxic properties.

139. GENETICS IV Classification of single gene disorders Autosomal dominant disorders Examples of AD diseases Famililal hypercholesterolemia 1/500 19p Von Willebrand disease 1/8000 12p Marfan syndrome 1/10000 15q Neurofibromatosis type I 1/3500 17q Huntington chorea 1/15000 4p Retinoblastoma 1/14000 13q Wilms tumor 1/10000 11p FAP 1/10,000 5q APKD 1/1000 16p

140. GENETICS IV Classification of single gene disorders Autosomal recessive disorders This is the single largest category of medelian disorders and most genetic metabolic diseases are inherited as autosomal recessive.

141. GENETICS IV Classification of single gene disorders Autosomal recessive disorders Features of AR disorders AR disorders result only when both alleles at a given locus are mutants. The trait does not usually affect the parents who are heterozygous and clinically normal but siblings may show the disease. Siblings have one chance in 4 of being affected ~ 25% risk for each birth.

142. GENETICS IV Classification of single gene disorders Autosomal recessive disorders Features of AR disorders If the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the proband is the product of a consanguineous marriage. AR traits are transmitted equally to males and females . Expression of the defect is more uniform than in autosomal dominant disorders.

143. GENETICS IV Classification of single gene disorders Autosomal recessive disorders Features of AR disorders Complete penetrance is common Recessive traits commonly present in childhood (in contrast to AD) Enzyme proteins are affected by a loss of txn . In heterozygotes , equal amounts of normal and defective enzyme are synthesized, and the individuals are normal clinically because ½ of enzyme complement is enough for normal txn .

144. GENETICS IV Classification of single gene disorders Autosomal recessive disorders Features of AR disorders Note that most mutant genes responsible for autosomal recessive disorders are rare in the general population, because those homozygous for the trait usually die before reaching reproductive age. However, a few lethal autosomal recessive diseases are common( e.g. SCA).

145. GENETICS IV Classification of single gene disorders Autosomal recessive disorders Examples of AR diseases Sickle cell anemia high freq 11p X- Thalassemia high 16p B- Thalassemia high 11p Cystic fibrosis 1/2500 7q phenylketonuria 1/10000 12q Wilson disease 1/50000 13q X1-antitrypsin def. 1/7000 14q Hereditary hemochromatosis1/1000 6p Albinism 1/20000 11q Glycose storage dxs etc

146. GENETICS IV Classification of single gene disorders X-linked disorders Expression of an X-linked disorder is different in males and females. Expression of a given trait is variable in females because they may be homozygous or heterozygous for that trait. Males are hemizygous for an x-linked and they invariably expressed the trait whether the trait is dominant or recessive.

147. GENETICS IV Classification of single gene disorders X-linked disorders All X-linked disorders can not be transmitted from father to son, but the father will donate his abnormal X-xsome to all his daughters, who are therefore obligate carriers of the trait. ** It is transmitted to the grandson through the carrier daughter of affected male.

148. GENETICS IV Classification of single gene disorders X-linked dominant traits Expressed mainly in the female Heterozygous woman transmits the disorder to half her children, whether male or female . A man with a dominant X-linked disorder transmits the disease only to his daughters.

149. GENETICS IV Classification of single gene disorders X-linked dominant traits Clinical expression of the disease tends to be less severe and more variable in heterogenous females than in hemizygous males. Examples Very few X-linked dominant disorders are described. E.g., Familial hypophosphatemic rickets.

150. GENETICS IV Classification of single gene disorders X-linked recessive traits Most X-linked traits are recessive. Heterozygous females do not have clinical disease . Characteristics Sons of women who are carriers have 50% chance of inheriting the disease. 50% of the daughters will be carriers.

151. GENETICS IV Classification of single gene disorders Characteristics ( Contd ) All daughters of affected men are asymptomatic carriers. Their sons do not have the trait. Symptomatic homozygous females can result from the rare mating of an affected man and an asymptomatic, heterozygous woman.

152. GENETICS IV Classification of single gene disorders Characteristics ( Contd ) Also heterozygous female may be affected if lyonization preferentially inactivate the normal X xsome. Expression of G6PD deficiency in females . The trait tends to occur in maternal uncles and in males cousins descended from the mother’s sisters.

153. GENETICS IV Classification of single gene disorders Examples Fragile X syndrome frequency in male Hemophilia A 1/2000 Hemophilia B 1/10,000 Duchene-Becker muscular dystrophy 1/70,000 Glucose-6-phosphate dehydrogenase def. 1/3500 X-linked agammaglobulinemia up to 30% X-linked severe combined immunodeficiency

154. GENETICS IV MULTIFACTORIAL INHERITANCE This describes a process by which a disease results from the effects of a number of abnormal genes and environmental factors. Most normal human traits are inherited as multifactorial and not as simple dominant or recessive pattern.

155. GENETICS IV MULTIFACTORIIAL INHERITANCE Most of the common chronic disorders of adults are multifactorial e.g. DM, hypertension, atherosclerosis, most cancers. Many births defects are also inherited as multifactorial e.g. Cleft lip and palate, pyloric stenosis, congenital heart disease.

156. GENETICS IV MULTIFACTORIAL INHERITANCE Multifactorial inheritance usually leads to familial aggregation that does not obey simple mendelian rules. They result from multiple genes that interact with each other and with environmental factors. Multifactorial inheritance is polygenic

157. GENETICS IV Characteristics of multifactoriial inheritance Expression of symptoms is proprtional to the number of mutant genes. Close relatives of an affected person have more mutant genes than the population at large. Environmental factors influence expression of the trait and concordance for the disease may occur in only one third of monozygotic twins.

158. GENETICS IV Characteristics of multifactoriial inheritance The risk in first-degree relatives (parents, siblings, children) is the same (5%-10%). The probability of disease is much lower in second-degree relatives. The probability of a traits expression in later offspring is influenced by its expression in earlier siblings. If one or more children are born with a multifactorial defect, the chance of its recurrence in later offspring is doubled .

159. GENETICS IV Characteristics of multifactorial inheritance The more severe a defect, the greater the risk of transmitting it to offspring . Some abnormalities characterized by multifactorial inheritance show a sex predilection. E.g., pyloric stenosis is more common in males, while congenital dislocation of the hip is more common in females.