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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

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  • 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

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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

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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

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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

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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

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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

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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

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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

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Autosomal recessive disorders

  • Some are associated with ethnic groups

    • beta thalassaemia Cypriots, Greeks, Italians

    • Sickle cell disease Africans, Blacks, West Indians

    • Cystic fibrosis Caucasians

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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

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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

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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

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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

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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

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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

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Chromosomal disorders

  • Autosomal chromosome disruptions are more serious than sex chromosomes disruptions

  • Deletions are more serious than duplications

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Chromosomal disorders

  • Chromosomal deletion disorders

    • Angleman syndrome

    • Prader-willi

    • Cri du chat

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Chromosomal disorders

  • Other disorders

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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

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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

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Multifactorial disorders

  • Examples

    • Hyperthyroidism

    • Multiple sclerosis

    • Psoriasis

    • Pyloric stenosis

    • Schizophrenia

    • Alzheimer’s

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Familial cancers

  • Who to refer CRC

    • 3 close relatives on same side of family with an associated tumour

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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

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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

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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

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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

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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

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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.

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Prenatal diagnosis

  • Investigations include

    • Chorionic villous sampling

    • Amniocentesis

    • Foetoscopy

    • ultrasound

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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

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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

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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

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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

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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%

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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

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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

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Genetics in Practice

  • Neurofibrmatosis

  • Sickle cell disease

  • Beta thalssaemia trait

  • Friedreichs ataxia

  • Facial scapulo humeral dystrophy

  • Beckers muscular dystrophy

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Genetics in Practice

  • Familial breast cancer – 3 families

  • Fragile x