Genetics

1. 2008 Genetics

2. Principles • Each Human cell has • 46 chromosomes = 23 pairs • Each pair consists of 1 paternal and 1 maternal chromosome • 2 genes at equivalent loci each coding for an individual polypeptide

3. Principles • Gametes (ova/sperm) has only 50% of parents genetic constitution • The particle randomly selected is one of the 2 genes at each loci • Heterozygote = 2 different allele (genes) at the same locus • Homozygote -= 2 identical alleles at the same locus

4. Classification of diseases • Diseases can be classified from defects in • Whole chromosomes – either number or form • Individual genes • Lots of genes and/or the environment

5. Autosomal disorders • 44 autosomes = 22 homologous pairs • 1 pair sex chromosomes • Genes have strict order on each autosome • Each gene occupies a distinct locus in unison with its counterpart of maternal/paternal origin • Alleles are alternative genes that have arisen by mutation

6. Autosomal disorders • If both members of a gene pair are identical then the individual is homozygous • If both members are different then the individual is heterozygous • Gene specified characteristics are called traits

7. Autosomal disorders • 3 types of autosomal disorder • Autosomal dominant – trait is seen in heterozygote Aa and homozygote AA • Autosomal recessive – trait is only seen in homozygote aa • Autosomal co-dominant – effect of both alleles seen in heterozygote AB

8. Types of autosomal inheritance • Autosomal dominant inheritance • Disorder manifest in both homo and heterozygote • Both sexes can be affected but their can be different degrees of severity = variable expression between individuals • Rarely an individual with a mutant gene may have a normal phenotype = non penetrance the gene and trait may still be transmitted to the offspring

9. Autosomal dominant disorders • 2,200 dominant disorders known • Dominant otosclerosis 3/1000 • Familial hypercholesterolemia 2/1000 • Adult polycystic kidney disease 1/1000 • Multiple exostoses 0.5/1000 • Huntingdon’s disease 0.5/1000 • Neurofibromatosis 0.4/1000 • Myotonic dystrophy 0.2/1000 • Polyposis coli 0.1/1000

10. Autosomal recessive disorders • Only appears in homozygote • Both parents usually heterozygote carriers • They are not affected by the disease • Incidence should be 1 in 4 of offspring • Affects each sex equally • Very little variability of expression • Parental consanguinity • A few are inborn errors of metabolism with defective enzymes

11. Autosomal recessive disorders • Some are associated with ethnic groups • beta thalassaemia Cypriots, Greeks, Italians • Sickle cell disease Africans, Blacks, West Indians • Cystic fibrosis Caucasians

12. Autosomal recessive disorders • 14,000 autosomal recessive traits known • Cystic fibrosis 0.5/1000 • Recessive mental retardation 0.5/1000 • Congenital deafness 0.2/1000 • Phenylketonuria 0.1/1000 • Spinal muscular atrophy 0.1/1000

13. Autosomal co-dominant inheritance • Can detect either or both of two alleles in an individual • The fragments can be followed through the family tree • Human blood groups ABO, duffy, kell, rhesus exhibit this form of inheritance

14. Autosomal co-dominant inheritance • ABO blood groups • If parents both AB then • Get offspring who are A, AB, B • But the ratio is 1(A) : 2(AB): 1(B) phenotype • If one allele is dominant and the other recessive would get 3:1 ratio

15. Chromosomal disorders • If mutations large enough to be seen under light microscope they are called chromosomal disorders • Divided into structural and numeric disorders • The smallest alteration to a chromosome that is visible is 4x106 base pairs

16. Chromosomal disorders • Affect 7.5% of all conceptions but due to miscarriage only affect 0.6% of live births • 60% of spontaneous miscarriages have chromosomal abnormalities • Commonest type of abnormalities are trisomies (Down’s, Edward’s), 45 (Turner’s), x or triploidy

17. Chromosomal disorders • Disorders result from germ cell mutations in parents that have been passed onto the sex chromosomes or autosomes in the affected individual • Arise out of somatic mutations in the generation affected

18. Chromosomal disorders • Autosomal chromosome disruptions are more serious than sex chromosomes disruptions • Deletions are more serious than duplications

19. Chromosomal disorders • Numeric disorders • 92 xxyy tetraploidy • 69 xyy triploidy • 47 xx (21) trisomy 21 • 47 xy (18) trisomy 18 • 47 xx (16) trisomy 16 • 47 xx (13) trisomy 13 • 47 xxy or xxxxy Klinefelters • 47 xxx trisomy x • 45 x Turner’s syndrome

20. Chromosomal disorders • Aneuploidy • Exists when the chromosome number is not 46 but not a direct multiple of the haploid number 23 • Caused by delayed movement of chromatid in the anaphase or non disjunction of chromosomes in metaphase • Occurs with increasing frequency with • Maternal age • Maternal hypothyroidism • During recent radiation or viral illness

21. Chromosomal disorders • Polyploidy • Occurs with a complete extra set or sets of chromosomes • Triploidy arises from • Fertilisation with 2 sperm or failure of one of the maturation divisions of the egg or sperm so producing a diploid gamete 69 xxy is the commonest • Tetraploidy is due to failure of first zygotic division

22. Chromosomal disorders • Trilpoidy • 69 xxy or more rarely xxx • 2% of all conceptions usually leads to miscarriage • If carries on to term • Low birth weight • Disproportionally small head to trunk • Syndactyly • Multiple congenital abnormalities • Large placenta with hydatidiform like changes

23. Chromosomal disorders • Tetraploidy • Describes a situation where the genotype is 96 xxyy or some other combination of sex chromosomes • Is rapidly fatal rarely survives to term

24. Chromosomal disorders • Trisomy • Is having 3 copies of a chromosome • Caused by failure of disjunction during meiosis with unequal separation of the chromosome between the gametes • Most are rapidly fatal only trisomy 21 survives beyond 1yr • Trisomy 13 – Patau’s syndrome severe mental retardation • Trisomy 18 – Edward’s syndrome

25. Chromosomal disorders • Sex chromosome abnormalities • Turner’s xo short stature webbed neck • Triple x xxx developmental delay tall • Double y xyy tall fertile psychiatric illness • Klinefelter’s xxy tall infertile early germ cell atrophy poor secondary sexual characteristics • Fragile x dominant x linked gene with 50% penetrance in females developmental delay

26. Chromosomal disorders • Structural disorders • Arise from chromosomal breakage, once broken attempted repair may rejoin 2 unrelated parts of the chromosome • Breakage facilitated by • Ionising radiation • Mutagenic chemicals • Some rare inherited conditions

27. Chromosomal disorders • Recognised structural abnormalities • Translocation the transference of material between chromosomes. Carriers with balanced translocations are not affected but offspring are • Deletion this occurs at both ends of a chromosome can lead to ring chromosomes • Duplication of a section of a small section of chromosome often with little harmful consequence

28. Chromosomal disorders • Recognised structural abnormalities • Inversion – breakage at 2 ends of a chromosome with rotation and rejoining of the part in between so that it lies the wrong way round • Isochrome – deletion of one arm of a chromosome with duplication of the other arm • Centric fragments – small remaining material after translocation

29. Chromosomal disorders • Chromosomal deletion disorders • Angleman syndrome • Prader-willi • Cri du chat

30. Chromosomal disorders • Other disorders

31. Multifactorial disorders • Phenotype is determined by the actions of multiple genetic loci and the environment • Risk in these families is higher than normal population it decreases with distance from affected individual • Twin concordance and family correlational studies are required if multifactorial inheritance is suspected

32. Multifactorial disorders • Examples • Spina bifida • Geographical differences indicate celtic descent • Seasonal variation and greater incidence in lower social class indicate an environmental influence also happening • Cleft palate and lip • CDH • Diabetes • epilepsy

33. Multifactorial disorders • Examples • Hyperthyroidism • Multiple sclerosis • Psoriasis • Pyloric stenosis • Schizophrenia • Alzheimer’s

34. Sex linked disorders • Women have two x chromosomes one from each parent one of which is inactivated at random • Males have only one x chromosome • X linked disorders can be dominant or recessive. In dominant disorders they are present in women as well as men

35. Sex linked disorders • Recessive x linked disorders • Only males affected • No variation of expression disease always follows predictable course • Heterozygous females are not affected but carry the gene • Rarely occurs in female only if faulty inactivation of the x chromosome

36. Sex linked disorders • 290 recessive x linked diseases are known • Red green colour blind • Fragile x • Duchenne muscular dystrophy • Becker muscular dystrophy • Haemophilia A factor 8 • Haemophilia B factor 9 • X linked agammglobulinaemia

37. Sex linked disorders • X linked dominant disorders • Expressed in both sexes but more common in females due to greater number of x chromosomes • Females may be homozygous or heterozygous • Males can only be heterozygous • Positive father will give trait to all his daughters but none of his sons • Positive mother will give trait to half her sons and half her daughters

38. Sex linked disorders • X linked dominant disorders • The trait is uniform seriousness in males • In females it has variable seriousness • Examples – very few known disorders • Xg blood group • Vitamin D resistant rickets • Rett’s syndrome

39. Digenic disorders • In these disorders two genes interact to produce the phenotype • Mode of inheritance is often simple mendelian but with another gene interfering to modulate the severity of the disease • Examples • Cystic fibrosis • Limb girdle dystrophy

40. Familial cancers • Examples • Breast • Ovarian • Colorectal • 5-10% of new cases are caused by dominantly inherited single gene mutations • Combinations of lower penetrance genes also contribute to a significant portion of family histories

41. Familial cancers • Features suggestive of inherited cancer • High incidence in family in closely related individuals • Early age of onset • Multiple primaries in an individual (rockenbach) • Certain cancer combinations • Breast and ovary • Breast and sarcoma • Colorectal, uterine, ovarian and stomach • Ethnicity – Ashkenazi Jews high incidence of 3 common breast and ovarian cancer founder mutations

42. Familial cancers • Who to refer with FH breast and ovarian cancer • Mother or sister breast ca < 40yrs • Mother or sister bilateral breast ca any age • Father or brother with breast ca any age • Mother or sister with breast and ovarian ca any age • One close relative with breast ca < 50 and relative with ovarian caany age same side of family

43. Familial cancers • FH breast and ovarian ca who to refer • Two close relative breast ca any age • Two close relative ovarian ca any age • Three or more close relative with breast ca, ovarian ca or both on the same side of the family at any age

44. Familial cancers • Who to refer colorectal cancer • 1 first degree relative CRC < 45yrs • 1 first degree relative who has 2 separate or multiple CRC or two associated ca – CRC, endometrial, ovarian, small bowel, ureter or renal pelvis. • 1 first degree relative with more than 1 bowel polyp < 40 which is tubulovillous, dysplastic, or an adenoma > 10cm

45. Familial cancers • Who to refer CRC cancers • 1 first degree relative with FAP of FH of FAP • 1 parent with multiple colorectal polyps >100 • 2 close relatives who are first degree relatives to each other can include both parents with average age < 70 of CRC • 2 close relatives who are first degree relatives to each other on same side of family with associated cancers age < 50

46. Familial cancers • Who to refer CRC • 3 close relatives on same side of family with an associated tumour

47. Familial cancers • High risk pedigrees • 4 close relatives with breast, ovarian, or both any age • 3 close relatives with breast ca average age < 60 • 2 close relatives with breast ca average < 50 • 2 close relatives ovarian ca any age • Known families of carriers of BRCA1, BRCA2

48. Familial cancers • High risk pedigrees • 3 close relatives CRC or 2 with CRC and one associated cancer in at least 2 generations. 1 must be under 50 at diagnosis and one should be first degree relative of the other 2 • Known gene carriers of hereditary non polyposis colon ca FAP or relatives of known affected family • All others are moderate risk

49. Familial cancers • Moderate risk pedigrees are normally managed in secondary care • Breast ca • Annual mammograms from age 40-50 then will enter national 3 yrly scheme • CRC • Offered colonoscopy frequency varies

50. Familial cancers • High risk pedigrees • Normally seen and counselled by regional genetic centre • Breast • Annual mammograms • If BRAC1 or 2 then combination of annual MRI and mammogram between ages 30-49yrs. Age 50-69 mammograms every 18 months then 3x/year after 69