Genetics Lecture 7.PDF

MD210 Genetics lecture 7: Epigenetics Mosaics - A mosaic is an individual who arose from a single fertilised egg, but who has 2 or more populations of cells each with different genotypes (Females are mosaics – 2X chromosomes - x-inactivation – some cells express X from mother, some express X from fa...

MD210 Genetics lecture 7: Epigenetics Mosaics - A mosaic is an individual who arose from a single fertilised egg, but who has 2 or more populations of cells each with different genotypes (Females are mosaics – 2X chromosomes - x-inactivation – some cells express X from mother, some express X from father) Clinical case – Gwen Dooley - 10 year old girl - Parents are quite tall - Born with puffy feet and hands - Scoliosis - Development normal, but small stature - Always smallest child in class Family History None of Gwen’s sibs or extended family show signs - Gwen’s lymphedema was apparent from birth, but small stature was only noticed from age of 5 Traits/Symptoms - Coarctation of aorta or bicuspid aortic valve - Webbed neck and lymphedema (sometimes) - Kidney problems – horseshoe kidney - Amenorrhea - Non-functional ovaries (streak gonads) – infertile - Non verbal learning disabilities and behavioural problems – variable Turner Syndrome (aka monosomy X) – causes - Turner syndrome occurs due to anaphase lag – where one sex chromosome moves too slowly to the pole of the daughter cell during division - It can happen: o During gametogenesis - classical monosomy X – 45,X o During early mitotic division - Turner Mosaicism – 45X/46XX or 45X/46XY (some are normal and some are missing a sex chromosome) o Neither is inherited Treatment options and priorities? - Depends on symptoms and level of mosaicism – screening and management of comorbidities o Heart problems o Scoliosis o Ear infections o High blood pressure o Thyroid o Bone loss - Neuropsychological and psychosocial issues - Hormone treatment - Infertility treatments Key investigations - Karyotype – translocation - Cardiac function tests - Cardiac imaging o CT, MRI, MRA - Y chromosome PCR Genetic counselling issues? - Impact of infertility o IVF and ERT - Not hereditary – reassurance for parents/Gwen - What if she is Y positive? (perform Y chromosome test and if necessary removal of streak gonads so they don't become malignant) - Transition of young people with TS to adult care o Advocacy and peer support o Ongoing multidisciplinary care Why is 45,X a problem? - X-inactivation is incomplete o Gene dosing - Up to 25% of X chromosome genes partially or totally escape (including PAR genes, e.g., SHOX) o Genes outside PARs may contribute to female phenotype - Escape genes expressed in higher levels in normal women versus Turner women Scenario - Mr and Mrs X - IVF Baby Born June 2014 - Healthy Male - Blood Group AB - Mother Group A (AA or AO) - Father Group A (AA or AO) - Cause? o They Took the Wrong Baby Home ? o Has Mrs X had another relationship ? But baby born by IVF o The Clinic Used the Wrong Sperm? Except they believe that this is Impossible o Paternity Test: ▪ Results Are Not Consistent With Mr X being the father ▪ More Detailed DNA Analysis Suggest Mr X is the Uncle - Mr X is a chimaera - Tetragametic Chimerism 2 Oocytes + 2 Sperm – 2 zygotes that merge into one organism - Mr. X has 2 genomes - Some cells carry the Allele A – make his red blood cells - Some cells carry the Allele B – but were not included in Mr X's haematopoietic tissue - Some of his brother’s cells were included in his gonads – carried his brother's genome Chimaerism vs Mosaicism - Chimaera = an individual with 2 or more populations of cells with different genotypes who arose by fusion of more than one fertilised zygote during embryogenesis (very rare) - Mosaic = an individual with 2 or more populations of cells with different genotypes who arose from a single fertilised egg - Usually result of a somatic change during early replication - Can be result of Germline mosaicism – occur early in germ cell development, resulting in a significant no. of gametes that carry the mutation and thus can affect >1 child Imprinting – Example – Robert Draper - Robert has an allele of Insulin Like Growth Factor 2 (IGF2) from Don (his father) – which works - He has an allele of Insulin Like Growth Factor 2 from Betty (his mother) that is switched off (imprinted) - If Robert has a child, which allele of the IGF2 gene will work? - It could be either- whichever allele, from either of his parents, that is in his sperm gets switched on – all imprinting is erased and rewritten with Roberts pattern in gonad's o 1. Roberts’ body cells ▪ Paternal IGF2 expressed (paternal methylation pattern) ▪ Maternal IGF2 imprinted (maternal methylation pattern) o Roberts’ primordial germ cells o Paternal and maternal methylation patterns deleted from both chromosomes o Roberts’ gametes ▪ Paternal imprint rewritten on both chromosomes in all sperm Why is this important? - IGF2 functions in regulating growth during gestation - If both alleles should begin to be expressed in a cell, that cell may develop into a cancer - E.g. Wilms’ tumour is an embryonic kidney cancer associated with loss of imprinting (LOI) of maternal IGF2 Angelman, Prader Willi and Imprinting - Both associated with a de novo deletion on long arm of Chr 15 (15q11-q13) - Both usually deletions for identical sets of genes but… - Deletion from paternal Chr 15 = Prader Willi - Deletion from maternal Chr 15 = Angelman Question: - What would a child with paternal uniparental disomy for Ch 15 have ? - Child is missing maternal Chr15 – Angelman's syndrome Prader-Willi & Angelman & Imprinting Errors - An affected individual may have BOTH maternal and paternal chromosomes - BUT – In Prader Willi Syndrome o the paternal chromosome may have maternal pattern of methylation (effectively no paternal chromosome) - In Angelman o The maternal chromosome may have the paternal pattern or methylation - Epigenetic (imprinting) error - Mutations in the imprinting control centre Things to remember - A mosaic is an individual who arose from a single fertilized egg, but who has 2 or more populations of cells each with different genotypes - Mosaicism is usually somatic, but can occur in the germline and then there is an increased risk for siblings and offspring - Chimaera = an individual with 2 or more populations of cells with different genotypes who arose by fusion of more than one fertilised zygote during embryogenesis - X-inactivation is incomplete - up to 25% of X chromosome genes partially or totally escape (including PAR genes), which has implications for gene dosing - Diseases related to imprinting can occur due to UPD or a mutation in the imprinting control centre, as well as deletion/mutation of the genes themselves on the relevant Chr