1 / 62

Genetics

2008. Genetics . 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. Principles. Gametes (ova/sperm) has only 50% of parents genetic constitution

Download Presentation

Genetics

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related