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Genetics - PowerPoint PPT Presentation

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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

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  • 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
  • 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
classification of diseases
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
autosomal disorders
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
autosomal disorders6
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
autosomal disorders7
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
types of autosomal inheritance
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
autosomal dominant disorders
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
autosomal recessive disorders
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
autosomal recessive disorders11
Autosomal recessive disorders
  • Some are associated with ethnic groups
    • beta thalassaemia Cypriots, Greeks, Italians
    • Sickle cell disease Africans, Blacks, West Indians
    • Cystic fibrosis Caucasians
autosomal recessive disorders12
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
autosomal co dominant inheritance
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
autosomal co dominant inheritance14
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
chromosomal disorders
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
chromosomal disorders16
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
chromosomal disorders17
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
chromosomal disorders18
Chromosomal disorders
  • Autosomal chromosome disruptions are more serious than sex chromosomes disruptions
  • Deletions are more serious than duplications
chromosomal disorders19
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
chromosomal disorders20
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
chromosomal disorders21
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
chromosomal disorders22
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
chromosomal disorders23
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
chromosomal disorders24
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
chromosomal disorders25
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
chromosomal disorders26
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
chromosomal disorders27
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
chromosomal disorders28
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
chromosomal disorders29
Chromosomal disorders
  • Chromosomal deletion disorders
    • Angleman syndrome
    • Prader-willi
    • Cri du chat
chromosomal disorders30
Chromosomal disorders
  • Other disorders
multifactorial disorders
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
multifactorial disorders32
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
multifactorial disorders33
Multifactorial disorders
  • Examples
    • Hyperthyroidism
    • Multiple sclerosis
    • Psoriasis
    • Pyloric stenosis
    • Schizophrenia
    • Alzheimer’s
sex linked disorders
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
sex linked disorders35
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
sex linked disorders36
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
sex linked disorders37
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
sex linked disorders38
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
digenic disorders
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
familial cancers
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
familial cancers41
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
familial cancers42
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
familial cancers43
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
familial cancers44
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
familial cancers45
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
familial cancers46
Familial cancers
  • Who to refer CRC
    • 3 close relatives on same side of family with an associated tumour
familial cancers47
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
familial cancers48
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
familial cancers49
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
familial cancers50
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
familial cancers51
Familial cancers
  • High risk pedigrees
    • Ovarian ca
      • Only offered if FH includes either ovarian ca or the person is a known BRAC carrier as part of UKFOCSS trial which offers transvaginal ultrasound and regular ca 125 monitoring every 4 months
    • CRC cancer
      • People at high risk of hereditary non polyposis crc and crc are offered 2 colonoscopies a year from ages 25-27 if they have been assessed as a positive pedigree
familial cancers52
Familial cancers
  • Summary
    • Family histories of cancer in primary care allows GP’s to assess risk and make appropriate referrals.
    • This allows families to benefit from relevant targeted screening and gene testing as per national guidelines.
prenatal diagnosis
Prenatal diagnosis
  • Investigations include
    • Chorionic villous sampling
    • Amniocentesis
    • Foetoscopy
    • ultrasound
prenatal diagnosis54
Prenatal diagnosis
  • Tests offered
    • Amniocentesis
      • Karyotyping for chromosomal abnormalities
        • Down’s syndrome
      • X linked disorders
        • Duchenne muscular dystrophy
      • Gene probes to detect individual genes
        • Cystic fibrosis
      • Enzyme assay of cultured amniotic cells
        • Inborn errors of metabolism
prenatal diagnosis55
Prenatal diagnosis
  • Risks of amniocentesis
    • Singleton preg 0.5-1% foetal loss
    • Multiple preg 3% risk foetal loss
    • Foetal damage very rare
      • Loss of one eye
      • damage to brachial plexus
      • Pneumothorax
    • Lung hypoplasia
prenatal diagnosis56
Prenatal diagnosis
  • Tests offered
    • Chorionic villus sampling
      • Same tests as performed on amniocentesis
    • Advantages
      • Performed earlier in preg it top needed done at much earlier stage before preg shows
      • Results available quicker
prenatal diagnosis57
Prenatal diagnosis
  • Chorionic villus sampling
    • Disadvantages
      • Greater risk of foetal loss 3%
      • Risk of foetal damage – limb agenesis due to disruption of foetal blood vessels
      • Chromosome analysis less accurate
      • Result sometimes can’t be interpreted requiring further tests
      • Genetic mosiaicism between chorionic cells and the foetus resulting in false positives and false negatives i.e. Down’ syndrome
prenatal diagnosis58
Prenatal diagnosis
  • Foetoscopy
    • Enables visualisation of foetus
      • Foetal inspection – facial and limb abnormalities
      • Foetal blood sampling – haemophilia, thalassaemia, sickle cell, fragile X, alpha 1 antitrypsin deficiency
      • Foetal skin biopsy – lethal epidermolysis bullosa
      • Foetal liver biopsy – ornithine transcarbamylase deficiency – loss = 5%
diagnosis in genetic counselling
Diagnosis in genetic counselling
  • If a major chromosomal abnormality exists then a recognised syndrome of 2 or more dysmorphic features will usually be present chromosomal analysis should be carried out if
    • Unexplained mental retardation
    • Known history of structural chromosomal problem
    • Unexplained stillbirth
    • Female with unexplained short stature
    • Recurrent miscarriages
    • Ambiguous sexual development
ethical and legal considerations
Ethical and legal considerations
  • Under congenital disabilities act 1976 an action can be taken against anyone whose negligent action resulted in a child being born disabled, abnormal or unhealthy.
  • It is the legal duty of all doctors to provide the most recent valid information about genetic disorders. If omitting to do so and on future pregnancy a foetal abnormality occurred the doctor would be liable to litigation
genetics in practice
Genetics in Practice
  • Neurofibrmatosis
  • Sickle cell disease
  • Beta thalssaemia trait
  • Friedreichs ataxia
  • Facial scapulo humeral dystrophy
  • Beckers muscular dystrophy
genetics in practice62
Genetics in Practice
  • Familial breast cancer – 3 families
  • Fragile x