Genetics for mrcog part1

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  • the defect is often in structural genes.
    no skip generation & + family history
    dominant = both male and female equally affected
    transmission of disease from either sex to either sex
    1 parent is enough to give the disease.
    look for consanguinity.
    new mutations are common.
    inheritance 1:2
    shows variable expression and incomplete penetrance
  • achondroplasia: fibroblast growth factor (fgf) 3 receptor defect.
    result in dwarfism, short limbs, normal sized head and trunk
    usually with advanced paternal age
  • Gene located on chromosome 4
    trinucleotide repeat CAG
    symptoms manifest at old age between 20 - 50
    example of anticipation in genetics
    findings: depression, prograssive demintia, choreform movements, caudate atrophy, decrease Ach and GABAin brain.
    In Huntington's disease, the HTT gene becomes elongated with a pathologically large number of C-A-G repeats, producing a protein consisting of large strings of glutamine called 'mutant-huntingtin'. Degradation products of this protein accelerate the breakdown of nerve cells in the basal ganglia and the cortex, producing the disease. The greater the number of repeats, the earlier the onset of the disease and the more affected an individual is.
  • shperiod RBC due to spectrin and ankrin defect
    hemolytic anemia and increase MCHC and spleenomegally
  • chromosome 16.
    90% of cases are due to mutation in APKD 1
    always bilateral, massive large cysts
    patients present with flank pain hematuria and renal failure
    accosiated with berry aneurysms, mitral valave prolapse
  • BRCA stands for breast cancer susceptibility gene.
    the BRCA 1 gene is found on chromosome 17
    BRCA 2 found on chromosome 13.
    both are tumor suppressor gene.
    mutations in each gene lead to defective form of the DNA repair protein, with the consequence of increased tumorigenesis
  • deletion in chromosome 5 (APC gene)
    colon becomes covered with with adenomatous polyps after puberty.
    progress to colon CA unless resecteed
  • rare multisystem genetic disease
    TSC1 gene -> hamartin chromosome 9
    TSC2 gene -> tuberin chromosome 16
    both tumor suppressor gene
    learning difficulties
    epilepsy
    cardiac rhabdomyomas
    renal angiomyolipomas
    brain abnormalities
    skin manifestations, ash-leaf spots, angiofibromas
  • often due enzyme deficiency
    skip generations usually seen in only 1 generation
    the 2 parents must be carriers
    inheritence 1:4 affected
    2:4 unaffected carriers
    1:4 normal
    often manifest in childhood
    commonly more severe than dominant disease
    not possible to trace using family history
  • disease of exocrine secretion
    increaes chloride in sweat
    carrier rate in caucasians 1:23
    prevalence is 1:2000
    mutation in CFTR gene on chromosome 7
    most common mutation is f508 in 70 %
    disease hallmark is viscid mucus production
    recurrent chest infections, pancreatitis, cirrhosis, IO, opsteoporosis, diabetes, infertility due to
    congenital absent vas deferens
    thick cervical mucus
  • causes by point mutation in Beta glob in chain in hemoglobin
    glutamic acid is replaced by valine
    prevelance in london 1: 500
    two types homozygous and heterozygous
    loss of RBC elasticity and sickling
    it has many complications but in pregnancy can lead to miscarriage, FGR, pre eclamsia
  • also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness)
  • often manifest very severely in males, frequently leading to spontaneous loss or neonatal death of affected male pregnancy.
    can transmit through both parents
    all daughters of the affected father are affected
  • trinucleotide repeat CGG
    X-linked defect affecting the methylation and expression of the FMR1 Gene on X chromosome associated with chromosomal breakage.
    the 2nd most common cause of genetic mental retardation after down syndrome
    findings: macro-orchidism (large testes), long face with large jaws, large everted ears, autism and mitral valve prolapse.
  • Blood groups are inherited from both parents.
    The ABO blood type is controlled by a single gene (the ABO gene) located on the 9 chromosome.
    codominance, which means that type A and B parents can have an AB child. A couple with type A and type B can also have a type O child if they are both heterozygous
  • X-linked = no male to male transmission and commonly more sever in males.
    recessive = it skip generations
    Obligate carriers:
    mothers of all affected sons.
    daughter of all affected men
    inheretince 1:2 sons of every carrier female
  • transmitted only through the mother
    both male and female is affected
    all offspring of the affected female are affected.
    disease are typically neuropathies and myopathies which requires more ATP and energy.
    sperms don’t contribute to the zygote beyond their nuclear DNA.
  • all disease with trinucleotide repeats have anticipation in common
    Huntington's disease is an example of genetic anticipation, a phenomenon where the disease can be progressively worse with each generation that inherits it. This is due to an incompletely understood process where the male copy of the gene has its number of repeats amplified during replication.
  • dysmorphic feature (small ears, up slanting palpebral fissures, flat facial profile, brachycephaly) single palmer crease, wide spaced big toe
    hypotonia
    conductive hearing loss
    cardiac abnormalities
    GIT abnormalities dudenal atrasia, imperforated anus, hirschprungs disease.
  • musculoskeletal: limb defects, rockerbottom feet, overlapping fingers.
    facial: micrognathia, cleft lip, cleft palate
    cardiac defect: VSD, ASD, PDA
    adbomenal defect: exomphalos, inguinal hernia, diaphragmatic hernia, renal malformations
  • midline defects: hypotelorism (abnormally decrease distance between eyes), holoprosencephaly (failure of the prosencephalon to develop into 2 hemispheres), cleft lip, cleft palate, scalp defects.
  • testicular atrophy
    gynecomastia
    female distribution of hair
    low testosterone
    high FSH and LH (hypergonadotrophic hypogonadism)
    Tall
    high pitched voice
  • short stature
    webbed neck
    wide carrying angle of arms
    wide shaped chest and wide spaced nipples
    edema in wrist and ankle in new born
    cystic hygroma in utero resulting in excess nuchal translucency
    1ry amenorrhea
    coarctation of aorta
    infertility and gonadal dysgenesis
    renal anomalies include horse shoe kidney
  • the concept of genomic imprinting suggests that in certain cases a genetic defect will only produce a phenotype if inherited from a particular parent.
  • pyloric stenosis, cancer, epilepsy, Alzheimer, thyroid, psoriasis,others
    a number of common disorders appear to have pattern of inheritance which involve a combination of genetic factors, drugs, environment and termed multifactorial inheritance.
  • Genoscopy: refers to different non-alleleic genotypes that result in similar phenotype.
    Heteroplasmy: presence of two or more different populations of mitochondria within a cell IncorrectIncorrect answer selected
    Isochromosome: refers to an abnormal chromosome created by deletion of one arm or duplication of the other arm.
    Syntheny: presence of genes on the same chromosome
    Autosome refers to non-sex (XY) chromosomes of which there are 22 pairs.
  • the total number of chromosomes is given first i.e 46
    the sex chromosomes are indicated next XY = for a male
    tranlocation is indicated by the letter ’t’ and is followed in parentheses by the number of chromosomes cornered with p or q
    so chromosome 2p21 swapped position with chromosome 3q29
  • Genetics for mrcog part1

    1. 1. GENETICS FOR THE MRCOG PART 1 YAZID JIBREL ROYAL MEDICAL SERVICES
    2. 2. • Clinical genetics is a speciality concerned with the investigating and diagnosis of patients of all ages with disorders that may be inherited
    3. 3. AUTOSOMAL DOMINANT 1. Achondroplasia 2. Huntigton disease 3. Von willbrand disease 4. heridetry spherocytosis 5. marfan syndrome 6. neurofibromatosis type 1 and 2 7. retinoblastoma
    4. 4. AUTOSOMAL DOMINANT 1. Achondroplasia 2. Huntigton disease 3. Von willbrand disease 4. heridetry spherocytosis 5. marfan syndrome 6. neurofibromatosis type 1 and 2 7. retinoblastoma
    5. 5. AUTOSOMAL DOMINANT 1. Achondroplasia 2. Huntigton disease [CAG] 3. Von willbrand disease 4. heridetry spherocytosis 5. marfan syndrome 6. neurofibromatosis type 1 and 2 7. retinoblastoma
    6. 6. AUTOSOMAL DOMINANT 1. Achondroplasia 2. Huntigton disease 3. Von willbrand disease 4. heridetry spherocytosis 5. marfan syndrome 6. neurofibromatosis type 1 and 2 7. retinoblastoma
    7. 7. AUTOSOMAL DOMINANT 8. von hippel lendeau disease. 9. Adult polycystic kidney disease 10. breast cancer. 11. acute intermittent porpheryia. 12. MEN 13. familial hypercholestrolemia 14. familial polyposis coli (AKA familial adenomatous polyposis).
    8. 8. AUTOSOMAL DOMINANT 8. von hippel lendeau disease. 9. Adult polycystic kidney disease 10. breast cancer. 11. acute intermittent porpheryia. 12. MEN 13. familial hypercholestrolemia 14. familial polyposis coli (AKA familial adenomatous polyposis).
    9. 9. AUTOSOMAL DOMINANT 8. von hippel lendeau disease. 9. Adult polycystic kidney disease 10. breast cancer. 11. acute intermittent porpheryia. 12. MEN 13. familial hypercholestrolemia 14. familial polyposis coli (AKA familial adenomatous polyposis).
    10. 10. AUTOSOMAL DOMINANT 15. AD deafness. 16. osteogenesis imperfecta. 17. Noonan’s syndrome. 18. myotonic dystrophy. 19. Tuberous sclerosis. 20. Ehler danlos syndrome. 21. heridetry hemorrhagic telagectasia (AKA oslerweber-rendau disease).
    11. 11. AUTOSOMAL RECESSIVE 1. Cystic fibrosis 2. Sickle cell disease 3. thalasemia 4. phenylketonuria (PKU) 5. Congenital adrenal hyperplasia 6. wilson’s disease. 7. Glycogen storage diseases.
    12. 12. AUTOSOMAL RECESSIVE 1. Cystic fibrosis 2. Sickle cell disease 3. thalasemia 4. phenylketonuria (PKU) 5. Congenital adrenal hyperplasia 6. wilson’s disease. 7. Glycogen storage diseases.
    13. 13. AUTOSOMAL RECESSIVE 1. Cystic fibrosis 2. Sickle cell disease 3. thalasemia 4. phenylketonuria (PKU) 5. Congenital adrenal hyperplasia 6. wilson’s disease. 7. Glycogen storage diseases.
    14. 14. AUTOSOMAL RECESSIVE 8. Tay sachs disease (AKA hexoaminidase A) 9. Gauchers disease. 10. homocystenuria 11. ataxia telangectasia 12. ARPKD (infantile PKD) 13. Albinism 14. hemochromatosis
    15. 15. AUTOSOMAL RECESSIVE 15. mucopolysacridosis (except hunter’s disease) 16. sphingolipidosis (except Fabry’s disease) 17. Usher syndrome 18. fredrich ataxia 19. spinal muscle atrophy 20. kartagner’s syndrome 21. wolfram’s syndrome
    16. 16. X-LINKED DOMINANT • we have 2 scenarios of inheritance: 1. the affected father 2. the affected mother • dominant = every generation (no skip generation) • X-liked = no male to male transmission
    17. 17. X-LINKED DOMINANT • dominant = every generation (no skip generation) • X-liked = no male to male transmission • male and female offspring are equally affected
    18. 18. X-LINKED DOMINANT • examples: 1. Fragiles X Syndrome. [CGG] 2. Rett syndrome. 3. hypophosphatemic rickets (perviously vitamin D resistant rickets) 4. incontinentia pigmenti. 5. Xg blood group.
    19. 19. codominanace inheritance neither of the two allele are dominant
    20. 20. X-LINKED RECESSIVE 1. Duchhennes muscular dystrophy 2. red green color blindness 3. G6PD 4. hemophilia (A, B, and C) 5. lesch-Nyhan syndrome (AKA HGPRT deficiency) 6. ichthyosis
    21. 21. X-LINKED RECESSIVE 7. Alport syndrome 8. wiskott aldrich syndrome 9. hunter’s syndrome 10. menke’s disease 11. fabry’s disease 12. nephrogenic diabetes insipidus
    22. 22. MITOCHONDRIAL INHERITANCE 1. mitochondrial myopathies 2. Leber’s hereditary optic neuropathy. 3. Leigh’s syndrome
    23. 23. TRINUCLEOTIDE REPEATS Disease Repeat huntington disease CAG fragile X syndrome CGG Myotonic dystrophy CTG friedreich ataxia GAA
    24. 24. ANEUPLOIDY • Aneuploidy, a deviation from the eupliod number, represents the gain (+) or loss (-) of a specific chromosome. • two major aneuploidies are observed: 1. monosomy (loss of chromosome). 2. trisomy (gain of chromosome)
    25. 25. DOWN SYNDROME • • Trisomy 21 • prevalance 1:700 live births • due to : 1. 1ry trisomy (nondysjunction) 95% 2. robertsonian translocation of chromosome 14 : 21 (3%). 3. mosaicism (1%) maternal age risk for down syndrome 1. 25 years old = 1 : 1500 2. 30 years old = 1: 900 3. 35 years old = 1:350 4. 40 years old = 1: 100 5. 45 years old = 1:30 6. 50 years old = 1:11 7. cut off for invasive screen 1:250
    26. 26. DOWN SYNDROME 1. increase risk for : alzheimer disease AML/ALL hypothyroidism 2. raised nuchal translucency
    27. 27. EDWARD SYNDROME • Trisomy 18 • increase nuchal translucency • musculoskeletal defect • facial defects • cardiac defects 1. 1 month = 30% • abdominal defects 2. 2 month = 50% • IUGR • • • male : female 1:2 UK prevalence 1:3000 live birth mortality rate: 3. 1 year = 90%
    28. 28. PATAU’S SYNDROME • • • • trisomy 13 • midline defects incidence increase with maternal age • post axial polydactyly • congenital heart defect • renal abnormality • omphalocele • IUGR UK prevalence 1:5000 live births mortality rate 100% by 1 month age.
    29. 29. KLIENFILTER SYNDROME • 47, XXY • incidence 1:1000 live birth
    30. 30. TURNER SYNDROME • 45,X or 45,XO • intellectually normal • risk for gonadoblastoma
    31. 31. DELETION microdeletion syndrome chromosome affected cri-du-chat 5 williams 7 angleman 15 prader-willi 15 smith magenis 17 Di-George 22
    32. 32. TRANSLOCATION • the exchange of 2 segments of chromosome between nonhomologous chromosomes • 2 types: 1. balanced: an even exchange of material with no excess or loss 2. unbalanced: unequal exchange in genetic material • Robetsonian translocation result from fusion of the long arms of 2 acrocentric chromosomes
    33. 33. TRANSLOCATION
    34. 34. TRANSLOCATION
    35. 35. IMPRINTING • Angelman 15q11-13 • maternal deletion 1. happy disposition 2. macroglossia 3. ataxia 4. seizures 5. learning difficulty • Prader-Willi 15q11-13 • paternal deletion 1. obese 2. hypogonadism 3. hypotonia
    36. 36. MULTIFACTORIAL INHERITANCE GENETIC Tuberculosis ENVIRONMENTAL Phenylketonuria Galactosaemia Rare Genetics simple Unifactorial High recurrence rate Spina bifida Ischaemic heart disease Ankylosing spondylitis Common Genetics complex Multifactorial Low recurrence rate • DM PreEclampsia • Club foot Pyloric stenosis Dislocation of hip Duchenne muscular dystrophy Peptic ulcer Diabetes HTN • Haemophilia Osteogenesis imperfecta • major NTD • congenital heart disease • cleft lip & palate. • Atopy • CDH Scurvy
    37. 37. INVESTIGATIONS • Karyotyping (chromosomal analysis) • FISH (molecular cytogenetics)
    38. 38. GENETICS LINGO • There is an agreed format for the describing chromosomal abnormalities and this forms the basis of reports from cytogenitic laboratory. • example: 46,XY,t(2;3)(p21;q29) • translocation: t • deletions: der • duplication: dup
    39. 39. THANK YOU

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