Genetics 1-7 Noura Houbby - PowerPoint Presentation

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Genetics 1-7

Noura Houbby

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Congenital defects: explain the classification of congenital defects, and how non-genetic factors may lead to such defects

SINGLE

MULTIPLE

Malformation

Disruption

Deformation Dysplasia

Sequence

Syndrome

Association

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MalformationPrimary structural defectSingle organ showing multifactorial inheritence Eg, atrial septal defect, cleft lip

DisruptionSecondary structural defect of organ/tissue Caused by ischaemia NOT genetic Extrinsic factor affects development Eg, amniotic band=> digital amputation

DeformationAbnormal mechanical force which distorts structure Later in pregnancy because organ works but has deformities Eg, club foot, hip dislocation

DysplasiaAbnormal organization of cells in tissueEg, thanatophoric dysplasia

SequenceMultiple abnormalities initated by PRIMARY factor (which can be genetic) eg, Potters sequence

SyndromeConsistent pattern of abnormalities with specific underlying cause eg, Downs syndrome

AssociationNon random occurrence of abnormalities NOT explained by syndrome Unknown cause eg, VATER association

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How do non-genetic factors lead to congenital defects?

Problems with chromosomesNumerical – aneuploidy, loss or gain of chromosomesStructural – translocations, deletions, insertions, inversions, ringsMosaicism – different cell lineages

Background:From one parent you inherit:22 autosomes (chr.1-22)1 sex chromosome (X or Y)Haploid number (23)One set from each parent =>Diploid number (46)

Structural

Normal in balanced translocations, unless:

•Disruption of a gene

•Fusion product, e.g., t(9;22)(q34;q11)àBCR-ABL àCML

Transfer of genetic material from one chromosome to another

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Aneuploidy

LOSS OR GAIN OF ONE OR MORE CHROMOSOMESMonosomy=loss of a single chromosome almost always lethalDisomy= normalTrisomy =gain of 1 chromosome can be tolerated for specific chromosomesTetrasomy=gain of 2 chromosomes, can be tolerated for specific chromosomes

Mosaicism

What does karyotype show?

46 chromosomes (22 autosomal, 1 sex) Males: 46,XY Females:46,XX

Chromosomes and chromosome abnormalities: recall the normal human karyotype, chromosome banding and nomenclature; explain what is meant by the terms “aneuploidy”, “chromosome translocation”, “copy number variant” and their possible biological effects.

 Where different

cells in the same individual have different numbers or arrangements of chromosomes

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Trisomy

+16 most common, but fatal in utero(#2 chromosomal cause of miscarriage)+13, +18, and +21 can be viable

Trisomy 21: Down syndrome

Trisomy 13:

Patau

syndrome

Heart defects (septaldefects, patent ductusarteriosus)Holoprosencephaly(cleft lip/palate, hypotelorism)Mental retardation

Trisomy18: Edwards syndrome

Heart defects (

septaldefects

, patent

ductusarteriosus

)

Kidney malformation (horseshoe kidney)

Digestive tract defects (

omphalocele

,

oesophageal

atresia)

Mental retardation

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Down syndrome: explain how three different chromosome aberrations lead to Down syndrome and the clinical features of that condition

1/700•Newbornperiod – hypotonia, lethargy, excess nuchal skin•Craniofacial – macroglossia, small ears, epicanthic folds, sloping palpebral fissures, Brushfieldspots•Limbs – single palmar crease, wide gap in 1st + 2nd toes•Cardiac – septal defects, atrioventricular canal•Other – short stature, duodenal atresia •Low IQ but ADVANCED SOCIAL SKILLS

Age effects:

recognise the increased genetic risks associated with advanced maternal and paternal age

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3 different chromosome aberrations leading to Down’s

Trisomy 21

90% time extra chromosome from mother

Non- disjunction of homologous chromosomes in meiosis 1 (3 copies of 21 instead of 2)

Break in acrocentric chromosomes (13,14,15,21,22) and fusion of long arms

- No of chromosomes still 46 but part/full copy of chromosome 21 attaches to another chromosome (usually 14)

Translocation

Diagnosed with mix of 2 types of cells- some containing 46 (normal) chromosomes some with 47 chromosomes

<1% cases of Downs

Mosaicism

Explain the basic principles of meiosis and non-disjunction

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Monosomy X: Turner’s SyndromeLoss of X or Y in paternal meiosis (other causes: ring chromosome, single arm deletion, mosaicism) PRENATALgeneralised oedema, neck swelling NEWBORN/CHILDoedematous hands/feet, webbed neck, low set ears, low posterior hairline, broad chest, short 4th metacarpals, aortic defects, urinary defectsADULT, complications short stature, ovarian failure => primary amenorrhoea + infertility, diabetes, hypothyroidismNormal intelligenceTreatments: Growth hormone, oestrogen replacement (MDT management)

Klinefelter’s Syndrome 47,XXY- Phenotypically male- 1:1000 male live births- Learning disability (IQ 80-90)- Taller than average (long lower limbs)- Gynaecomastia- Infertility- Risk of leg ulcers, osteoporosis and breast carcinoma in adult lifeX chromosome can be from either parentRare variants: 48,XXXY and 49,XXXXY

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Dosage compensation: define dosage compensation and explain why sex determination is not solely based on sex chromosome karyotype

Dosage compensation: process by which organisms equalize expression of genes between members of different biological sexesMechanisms: Random inactivation of single X chromones in females (most mammals) Increased (2x) expression of X chromosome genes in malesDecreased (0.5x) expression of both X chromosome genes in hermaphrodites

BUT it is possible to be chromosomally one gender and phenotypically the opposite

Females: XXMales: XY

SRY

gene => testes development

Can be

translocated

to

X chromosome

in

SRY recombination

XX males develop testes but are sterile because other Y chromosome genes important in

spermatogenesis

XY females infertile

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Genetic disease

Monogenic disordersComplex disordersClear inheritanceNo clear inheritanceNo environmentEnvironment essentialIndividually rareCommonHuntingtons, CF, HaemophiliaType 2, Schizophrenia, Crohn’s

Allele - alternate form of gene Mutation- heritable change in DNA sequencePolymorphism= mutation at >1% frequency in given population.•Polymorphisms can contribute to complex disease•Only called mutation if contributes to monogenic diseasePoint mutation – missense + nonsenseFrameshift mutation – insertions or deletions

BASICS

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Segregation analysis: explain the utility of familial segregation analysis, summarise a family history by generating a pedigree diagram.Risk assessment: generate a genetic risk assessment based on pedigree analysis.

Why are pedigree diagrams important?

•Identify genetic disease running in family•Identify inheritance patterns•Aid diagnosis•Assist in management of condition•Identify relatives at risk of disease

Mendelian inheritance patterns: Autosomal dominant Autosomal recessive X linked dominant (rare) X linked recessive Mitochondrial

Modes of inheritance: list examples of recessive and dominant autosomal and X-linked disorders and explain their segregation patterns; explain mechanisms of dominance, co-dominance and

recessivity

and their implications for therapy.

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AUTOSOMAL DOMINANT

At least one parent affected Transmitted by M or F M or F affected Vertical transmission

AaaAaaaaAaaa

Huntington’s diseaseMotor, cognitive + psychiatric dysfunction ‘hyperkinesia’35-44 yrs old. Survival: 15-18 yrs Treatment eases symptoms, no cureCell death in basal gangliaCaused by INSTABLE CAG triplet repeats which may expand with generations

AUTOSOMAL RECESSIVE

No affected parent Transmitted by M or F M or F affected Usually no family history

AaAAAAaaAaaa

Cystic fibrosisChronic life-threatening conditionSymptoms: mucus in lungs affects lung function, blockages in pancreas Treatment: daily enzymes, physio1 in 22 in UK carrierMutation in CFTR gene on Ch 7 (encodes Cl- channel). Disruption salt/water regulation => thick mucus + symptoms

10-35 repeats: unaffected

27-35 repeats: unaffected, but at risk of having affected child35-40 repeats: sometimes affected, sometimes not40-120 repeats: affected

Down generation: age of onset decreases, severity increases

SAME GENE, DIFFERENT SYMPTOMS:

CAVD causes infertility

Most cases caused by mutation in CFTR gene

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X-LINKED RECESSIVE

No affected parentsTransmitted by carrier F Only M affected

HaemophiliaBlood clotting disorder => easy bruising, heavy bleeding 2 types: Haemophili A + B (rarer)Treatment: clotting factor injectionsHaemophilia A: F8=> coagulation factor 8Haemphilia B: F9=> cogulation factor 9(Both genes on X chromosome)

XxXXXXxYXYxY

GENETIC HETEROGENEITY

Some important definitions….

Incomplete penetrance

– symptoms are not always present in an individual with a disease-causing mutation

Variable expressivity

– disease severity may vary between individuals with the same disease-causing mutation

Phenocopy

– having the same disease but with a different underlying cause

Epistasis

– interaction between disease gene mutations and other modifier genes can affect phenotype

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• Modes of inheritance: list examples of recessive and dominant autosomal and X-linked disorders and explaintheir segregation patterns; explain mechanisms of dominance, co-dominance and recessivity and their implications for therapy.

Dominant conditions

Mutations => toxic protein- effects of mutated gene ‘mask’ normal copy

Treatment: neutralize toxic protein effects or ‘switch off’ mutant gene

Recessive conditions

Mutations => absence of functional protein- normal copy absent

Treatment: restore activity of missing protein by replacing gene/protein product/affected tissue

Codominant conditions

Mutations => affect both mutated and normal genes apparent in people with both eg, sickle cell trait

What is genomic imprinting?

Epigenetics and genomic imprinting: explain what is meant by epigenetics; list two specific examples of genomic imprinting disorders, outlining possible mechanisms, clinical features and transmission patterns.

Inherit two copies of their genes—one from mother and one from father

Usually both copies of each gene are active but sometimes 1 copy turned onWhich copy is active depends on parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s motherTHIS IS genomic imprinting.Methylation identifies which copy of gene was inherited from which parent 2 major clusters of imprinted genes: short (p) arm of chromosome 11 (at position 11p15) long (q) arm of chromosome 15 (in the region 15q11 to 15q13).

Uniparental

disomy

(UPD)

occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. 

2 examples:

Prader

Willi Syndrome

and

Angelman

Syndrome

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Chr 15 imprinting disorders

PRADER- WILLI SYNDROME(loss of paternal)

ANGELMAN SYNDROME(loss of maternal)

Symptoms:

Hyperphagia => obesity Mental impairment Behavioural problemsMuscle hypotonia Short stature, small hands + feet Delayed/ incomplete puberty, infertility

Management: Hyperphagia= diet restriction Exercise to increase muscle mass GH for short stature Hormone replacement at puberty

Symptoms: Developmental delay + speech impairment Movement disorder (ataxia, tremulous limb movement)Behavioral uniqueness: happy demeanors, excitable, short attention span Microcephaly Seizures (<3 yrs onset)

Management:

Symptomatic- anticonvulsant, physio, communication therapy

Normal life span

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Mitochondrial genome37 genes encoding resp complexes, tRNA, rRNA2-10 copies per mitochondriun

Mitochondrial inheritance Transmitted through females via oocytes Both M + F affected Phenotype variable due to heteroplasmy

Mitochondrial disorders

Progressive, ultimately fatal:

Muscle weakness, vomiting, episodic seizures and headache, hemiparesis, dementia

Diagnosis:

muscle biopsySymptomatic treatment Genetics: single mutations in several genes

MELASMitochondrial Encephalopathy Lactic Acidosis and Stroke-like episodes

LHONLebers Hereditary Optic NeuropathyMore common in males???Degeneration of retinal ganglion cells Bilateral, painless, loss of central vision + optic atrophy 20 yrs = average age of onset Most patients eventually become blind

Diagnosis: ophthalmology findings + blood test for mtDNA mutations Symptomatic treatment

Mitochondrial disorders: list two examples of mitochondrial disorders, explaining transmission patterns and the implications of

heteroplasmy

for counselling.

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UK Newborn Screening programmePhysical exam Hearing test Blood spot test for genetic diseases – many FOCUS on: PKU + MCADD

Phenylketonuria PKUPhenylalanine hydroxylase (PAH) def>600 genetic mutations described SYMPTOMS:- Blond hair/blue eyes (no melanin)- Eczema, must odour (excess phenylacetate) TREATMENT: Early detection Remove phenylalanine from diet + monitor levels Protein supplements to supply other amino acids Strict diet in pregnancy (risk of growth retardation + heart defects)UNTREATED: seizures + severe mental retardation

MCADD deficiency

Most common disorder of fatty-acid oxidation MCAD = Medium-Chain Acyl-CoA DehydrogenaseMutation in ACADM gene (85% A985G)Presents in infancy with:Episodic hypoketotic hypoglycaemiavomiting, coma, metabolic acidosis, encephalopathyUndiagnosed => 25% mortality of first episodeMechanismAsymptomatic at baselineFasting or metabolic stress  switch to fatty acid oxidation, but impairedHypoglycaemiaHypoketosisTreatment:Avoiding fastingNutritional supplements at times of increased stress

Genetic screening: list two examples of inborn errors of metabolism currently included in UK national neonatal screening

programmes

, including clinical features and therapeutic management of each condition.

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Indications for testing: list the indications for referral to Genetics Services regarding prenatal testing.

Reproductive options: explain the reproductive options available, summarise the psychosocial aspects associated with reproductive decision making.

Following abnormal findings at nuchal scan or mid-trimester scan Following results of combined test which give an increased risk of Down SyndromeIf previous pregnancy affected with a condition e.g. DS, CFIf parent(s) carrier of chromosome rearrangement or genetic condition, e.g. t(13;14), DMD, HD.FH of genetic condition

What is the combined test for Down’s?

Combined test =levels of the hormone free beta-hCG +protein PAPP-ADown’s babies HIGH hCG and LOW levels of PAPP-A.

Planning prenatal testing

Facilitating decision making

Seeing patients in clinic following diagnosis in utero

Arrange termination if necessary

Discuss recurrence risks and plans for future pregnancies

Taking into account: previous experiences, family situation, personal beliefs, psychosocial situation, miscarriage risk with genetic risk

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Non-invasive versus invasive tests: explain the use of non-invasive tests (maternal serum screening, ultrasound, NIPT) and the use of invasive tests (amniocentesis, chorionic villus sampling).

Prenatal tests

INVASIVE

NON- INVASIVE

Maternal serum screening

Serum markers in blood can detect increased risk of trisomy 21, 18 and/or neural tube defects

Ultrasound cffDNA (cell free fetal DNA)Analyses DNA fragments in maternal plasma during pregnancy – 10-20% comes from placenta and is representative of unborn baby (maternal blood test => accurate at 9weeks)

AmniocentesisFrom 16 weeks Sample of amniotic fluid which contains fetal cells 1% miscarriage risk, infection, Rh sensitisationChorionic villus sampling11-14 weeks, 1-2% miscarriage risk Transabdominal or transvaginal Sample of chorionic villi-part of developing placenta- same DNA as fetus Earlier result than amnio

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Mutations in cancer: explain the difference between somatic and germline mutations, and between driver and passenger mutations; summarise the evidence about the number of mutations of different types found in cancer cells.

What is the difference between somatic and germline mutations?Somatic- occur in body cells, cannot be passed to offspring (90% cancers) Germline- mutations in gametes, can be passed onto offspring

What is the difference between driver and passenger mutations?

Inherited cancer disorders:Familial adenomatous polyposisThousands intestinal  polyps,  one  or  more  of  which  is  likely  to  become  cancerous>1%  of  all  colorectal  cancers  Mutation  of  APC  (adenomatous  polyposis  coli)  gene . APC  controls  cell  division  Virtually  100%  lifetime  risk  of  cancerHNPCC (hereditary non polyposis colorectal cancer)3%  of  all  cases,    Most  common  inherited  form  (90%  of  familial  cases)  Mutation  of  MLH1  or  MSH2  (DNA  repair  genes)  Lifetime  risk  of  cancer  80%

Passengers - mutations that don't contribute to the development of cancer but have occurred during growth of cancerDrivers- contribute to cancer development

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Oncogenes and tumour suppressor genes: explain what oncogenes and tumour suppressor genes are, and why they are important in cancer.

OncogenesProto-oncogenes: promote growth + proliferation in cellsActivated into overdrive => oncogenes Signalling cascades + mitogenic pathway activationExamples: growth factors, transcription factors, tyrosine kinasesGAIN OF FUNCTION

Tumour suppressorsRegulate cell division, DNA damage checkponits, apoptosis, DNA repair Mutations => lose function=> faulty cell divisionLOSS OF FUNCTION

Eg

, Hit 1= inherited BRCA1/2 then second hit is somatic

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Chromosome rearrangements in cancer: outline the contribution of chromosome rearrangements to the formation of gene fusions and their contribution to oncogenesis; explain how chromosome translocations are used to quantify residual disease in leukaemia.

Translocations: if 2 intragenic regions fuse= new genes with potentially oncogenic properties can ariseExample: chronic myeloid leukaemia Clonal myeloproliferative disorder => overproduction of mature granulocytes Middle ages/elderly 3 phases: chronic (benign), accelerated (omnious), blast crisis (acute leukaemic, invariably fatal)Philadelphia chromosome >90% t(9,22)= BCR-ABL1 fusion protein (tyrosine kinase)Chemotherapeutic targets: Imatinib (blocks ATP binding site of BCR-ABL1)No Philadelphia chromosome = BAD

KRAS test with

cetuximab

for colorectal cancer

KRAS mutation = less likelihood of response

EGFR test with

gefitinib

for

nonsmall

-cell lung cancer

EGFR mutation = greater likelihood of response

BCR-ABL1 “T315I” test with

dasatinib

for chronic myeloid leukaemia

BCR-ABL1 T315I mutation = unlikely to respond

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Obesity: list defects in the leptin-melanocortin pathway leading to three forms of monogenic obesity.

What is leptin?Hormone made by adipocytes in white adipose tissue Circulates in plasma in proportion to amount of adipose tissueActs on hypothalamus (arcuate nucleus) => inhibits appetiteLOW when LOW body fat HIGH when HIGH body fat

Monogenic leptin deficiency: Hunger, obesity, no puberty, poor growth, low thyroid, immune problems

Other genes in same pathway that cause single gene obesity

DominantMC4R – most common single-gene form of obesity (2-6%) RecessivePCSK1 – obesityPOMC – red hair, obesity, adrenal insufficiencyMRAP2 - obesityALL AFFECT APPETITE REGULATION

TYPES OF OBESITY

Syndromic obesity

Monogenic obesity

Common obesity

Eg, Prader Willi syndrome

- Dominant of recessive single gene disorders => obesity

- Obesity in general population

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Heritability: identify heterogeneity in complex genetic disease, explain how we can estimate the heritability of a common complex disease.

Obesity: explain how genome-wide SNP association studies are designed and their contribution to our understanding of obesity; identify the contribution of copy number variants to obesity; explain the implications of genetics for clinical management of obesity.

Clinical management of obesity: Lifelong prevention + lifestyle measuresMedication Bariatric (weight loss) surgery

Common obesity-

obesity in the general population

Genome- wide association studies (GWAS) Hypothesis free, common disease= common variant, see if disease statistically associated with SNPs (single nucleotide polymorphisms)Findings: GWAS identified SNPs explain only small proportion of common obesity risk

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Next generation sequencing: explain the principles of next generation sequences, and how it differs from Sanger sequencing

New molecular defects: explain how modern DNA sequencing technology is being used to determine molecular basis of monogenic diseases

Personalised/precision medicine: list examples of how advances in genomic medicine may lead to personalised/precision medicine, including the treatment of cancer

PCR for diagnosis of genetic disease eg, for CFPreimplantation diagnosis for IVF embryos (PCR specific genes) Mitochondrial transfer (3 parent babies)

Future: genetic editing? To treat monogenic diseases

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https://bit.ly/2Lcia1i

Thankyou

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