The subject and the main tasks of Medical Genetics. Role of heredity in human pathology

1. The subject and the main tasks of Medical Genetics. Role of heredity in human pathology Furdela Victoria MD. Assistant Pediatrics Department #2

2. General consideration Geneticsisthesciencethatdealswithheredityandvariationinorganisms, includingthegeneticfeaturesandconstitutionof a singleorganism, species, orgroup, andwiththemechanismsbywhichtheyareeffected

3. - Environment - Genes Genetic variations cause inherited diseases Diseases with hereditypredisposition Environmental Diseases Genetic Diseases - Cystic fibrosis - Down syndrome - Sickle cell disease - Phenilcetonuriae • Infection • Traumas • burns - Cardiovascular Disease - DM type 2 - cancer

4. Genetic Information • Gene – basic unit of genetic information. Genes determine the inherited characters. • Genome – the collection of genetic information. • Chromosomes – storage units of genes. • DNA - is a nucleic acid that contains the genetic instructions specifying the biological development of all cellular forms of life

5. Locus1 Possible Alleles: A1,A2 Locus2 Possible Alleles: B1,B2,B3 Chromosome Logical Structure • Locus – location of a gene/marker on the chromosome. • Allele – one variant form of a gene/marker at a particular locus.

6. Human Genome Most human cells contain 46 chromosomes: • 2 sex chromosomes (X,Y): XY – in males. XX – in females. • 22 pairs of chromosomes named autosomes.

7. Glossary & Definitions • Phenotype - the physical description of the character in an individual organism • i.e a green eyes • Genotype - the genetic constitution of the organism • Mutation - a change in the genetic material, usually rare and pathological • Polymorphism - a change in the genetic material, usually common and not pathological

8. The colure of eyes, the colour of skin is heredity

9. The colour and structure of our hair is also heredity

11. Glossary and Definitions • Homozygote- an organism with two identical alleles • Heterozygote- an organism with two different alleles • Hemizygote - having only one copy of a gene • Males are hemizygous for most genes on the sex chromosomes

12. Chromosome Structure sister chromatids telomeres centromere unreplicated replicated chromosome chromosome Each chromatid consists of a very long strand of DNA. The DNA is roughly colinear with the chromosome but is highly structured around histones and other proteins which serve to condense its length and control the activity of genes. a a

13. Key chromosomal regions Centromere A region within chromosomes that is required for proper segregation during meiosis and mitosis. Telomeres Specialized structures at chromosome ends that are important for chromosome stability.

14. Chromosomes can be classified according to size and form, and numbered of large to small. These classified chromosomes form a karyotype.

16. Human genetic diseases and normal variations can be placed into one of five categories: • monogene disorders (diseases or traits where the phenotypes are largely determined by the action, or lack of action, of mutations at individual loci); • multifactorial traits (diseases or variations where the phenotypes are strongly influenced by the action of mutant alleles at several loci acting in concert); • chromosomal abnormalities (diseases where the phenotypes are largely determined by physical changes in chromosomal structure - deletion, inversion, translocation, insertion, rings, etc., in chromosome number - trisomy or monosomy, or in chromosome origin - uniparentaldisomy); • mitochondrial inheritance (diseases where the phenotypes are affected by mutations of mitochondrial DNA); and • Congenital malformations(congenital defects of inner organs or parts of body)

17. Problems with Chromosome Structure: • Deletion – during cell division, especially meiosis, a piece of the chromosome breaks off, may be an end piece or a middle piece (when two breaks in a chromosome occur). • Inversion – a segment of the chromosome is turned 180°, same gene but opposite position • Translocation – movement of a chromosome segment from one chromosome to a non-homologous chromosome • Duplication – a doubling of a chromosome segment because of attaching a broken piec form a homologous chromosome, or by unequal crossing over.

18. Problems with Chromosome Number • Monosomy – only one of a particular type of chromosome (2n -1) • Trisomy – having three of a particular type of chromosome (2n + 1) • Polyploidy – having more than two sets of chromosomes; triploids (3n = 3 of each type of chromosome), tetraploids (4n = 4 of each type of chromosome).

19. Chromosomal disorders • Addition or deletion of entire chromosomes or parts of chromosomes • Typically more than 1 gene involved • 1% of paediatric admissions and 2.5% of childhood deaths • Classic example is trisomy 21 - Down syndrome

20. Down Syndrome KARYOTYPE

21. Single gene disorders • Single mutant gene has a large effect on the patient • Transmitted in a Mendelian fashion • Autosomal dominant, autosomal recessive, X-linked, Y-linked • Osteogenesis imperfecta - autosomal dominant • Sickle cell anaemia - autosomal recessive • Haemophilia - X-linked

22. Polygenic diseases • The most common yet still the least understood of human genetic diseases • Result from an interaction of multiple genes, each with a minor effect • The susceptibility alleles are common • Type I and type II diabetes, autism, osteoarthritis

23. What about mapping polygenic disorders? Environment Gene1 Gene 2 Gene 3 Gene 4 PHENOTYPE

24. Polygenic diseases are common Unrelated affected individuals share ancestral risk alleles

25. Gregor Mendel: “Father of Genetics” While assigned to teach, he was also assigned to tend the gardens and grow vegetables for the monks to eat. Augustinian Monk at Brno Monastery in Austria (now Czech Republic) Not a great teacher but well trained in math, statistics, probability, physics, and interested in plants and heredity. Mountains with short, cool growing season meant pea (Pisum sativum) was an ideal crop plant.

26. Two fundamental laws derived from Mendel’s work 1. The Law of Segregation: Genes exist in pairs and alleles segregate from each other during gamete formation, into equal numbers of gametes. Progeny obtain one determinant from each parent. 2. The Law of Independent Assortment Members of one pair of genes (alleles) segregate independently of members of other pairs.

27. After rediscovery of Mendel’s principles, an early task was to show that they were true for animalsAnd especially in humans

28. Problems with doing human genetics:Can’t make controlled crosses!Long generation timeSmall number of offspring per crossSo, human genetics uses different methods

29. Chief method used in human genetics is pedigree analysisI.e., the patterns of distribution of traits in kindreds

30. Pedigrees give information on:Dominance or recessiveness of allelesRisks (probabilities) of having affected offspring

31. Standard pedigree symbols Male, affected Male, heterozygous for autosomal recessive trait Female, unaffected Female, heterozygous for Autosomal or X-linked recessive trait Male, deceased Dizygotic (non-identical) twins Mating Monozygotic (identical) twins Consanguineous mating Spontaneous abortion or still birth Pregnancy

32. Standard symbols used in pedigrees

33. Medical Genetics When studying rare disorders, 5 general patterns of inheritance are observed: • Autosomal recessive • Autosomal dominant • X-linked recessive • X-linked dominant • Mitochondrial

34. Autosomal dominant • the locus is on an autosomal chromosome and only one mutant allele is required for expression of the phenotype • Affected males and females appear in each generation of the pedigree. • Affected mothers and fathers transmit the phenotype to both sons and daughters. • e.g., Marfan disease.

35. Autosomal DominantFirst pedigree of this type:Farabee 1903Brachydactyly

36. Autosomal DominantMost dominant traits of clinical significance are very rareSo, most matings that produce affected individuals are of the form:Aax aa

37. Autosomal recessive • the locus is on an autosomal chromosome and both alleles must be mutant alleles to express the phenotype • The disease appears in male and female children of unaffected parents. • e.g., cystic fibrosis

38. Autosomal recessiveAffected persons must be homozygous for the disease alleleThese are likely to be more deleterious than dominant disorders, and so are usually very rareThus, the usual mating is:Aax Aa

39. X-linked dominant • Affected males pass the disorder to all daughters but to none of their sons. • Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters

40. X-linked recessive • Many more males than females show the disorder. • All the daughters of an affected male are “carriers”. • None of the sons of an affected male show the disorder or are carriers. • e.g., hemophilia • If the locus is on the X chromosome and both alleles must be mutant alleles to express the phenotype in females

41. Mitochondrial inheritance • This type of inheritance applies to genes in mitochondrial DNA • Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. • E.g. Leber's hereditary optic neuropathy (LHON)

42. A polygenic phenotype An affected individual with unaffected parents Affected individual joining the family, emphasizing the common nature of the disease No clear inheritance pattern

43. General features of heredity pathology • Genetic anamnesis (presents of heredity family diseases, infant death, abortions, fetus death, long barrenness) • Dysmorphic signs • Low birth weight • High morbidity and mortality • Mental retardation • Ocular and ear defects • Skeleton abnormalities • Abnormalities of internal organs

44. Example of dysmorphic signs

45. Example of dysmorphic signs

46. Mongoloid eyes Antimongoloid eyes

47. Genetic counseling

48. Indicationsfor genetic counseling • Child with congenital pathology • Congenital pathology in one of parents • Congenital pathology in relatives • Abnormalities of pregnancy

49. Methods of genetic counseling • Drawing the pedigree or family tree • Cytogenetic method • Prenatal diagnostics • Method of dermatoglyphics • Population-statistic method • Examination of twins

50. Drawing of pedigree • It is importantto draw the pedigree or family. This method helps to show the number of involved family members, their sexes and ages of onset etc. • to determine the type of inheritanceand further chances of recurrence of the inherited disorder.