Genetic Implications of Tetralogy of Fallot Dr Verity

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Genetic Implications of Tetralogy of Fallot Dr. Verity Hartill ST 6 Dr. Ros Jewell

Genetic Implications of Tetralogy of Fallot Dr. Verity Hartill ST 6 Dr. Ros Jewell Cons Dept of Clinical Genetics Leeds

A bit about us in genetics… Genetic conditions related to To. F Plan Implications

A bit about us in genetics… Genetic conditions related to To. F Plan Implications of a genetic diagnosis for children and adults Management of genetic conditions Testing for potential genetic basis of To. F Counselling for adults with To. F considering having children

Yorkshire Regional Genetics Service • • 10 Consultants 4 Sp. R numbers 18 Genetic

Yorkshire Regional Genetics Service • • 10 Consultants 4 Sp. R numbers 18 Genetic Counsellors Admin staff, including research coordinators and family history administrators • Molecular laboratory – (Cyto and DNA)

Where are we? Part of Pathology Directorate • Clinical dept; Chapel Allerton Hospital •

Where are we? Part of Pathology Directorate • Clinical dept; Chapel Allerton Hospital • Laboratories; Bexley Wing, SJUH Catchment area; North, East, West Yorkshire & North Lincolnshire Nationally; 23 regional genetics services

Chromosomes and genes • • 23 pairs of chromosomes Each chromosome is like recipe

Chromosomes and genes • • 23 pairs of chromosomes Each chromosome is like recipe book Each recipe is gene 20, 000 genes in human genome

Chromosomes • Array CGH/ SNP array Current Genetic testing Genes • Single gene tests

Chromosomes • Array CGH/ SNP array Current Genetic testing Genes • Single gene tests • Panel tests • Whole exome sequencing • Whole genome sequencing

Genetics in Medicine today

Genetics in Medicine today

Case study 1 • 5 month old • Tetralogy of Fallot • Mild developmental

Case study 1 • 5 month old • Tetralogy of Fallot • Mild developmental delay • Feeding problems • Poor weight gain • Recurrent chest infections • Mild dysmorphic features • Di George syndrome • 22 q 11 deletion syndrome

Di George syndrome (22 q 11 del) • • • • Learning delay and

Di George syndrome (22 q 11 del) • • • • Learning delay and behavioural problems Speech and hearing problems Cleft palate or VPI Feeding difficulty CHD 75%, 20% To. F Hypoparathyroidism - hypocalcaemia Seizures Immune dysfunction (cell mediated immunity) Scoliosis Short stature Mental health problems eg schizophrenia (20%) Distinctive facial features Renal anomalies (renal agenesis, VUR) Very variable

Management in Di George syndrome - Children (Nowgen guidelines) • • Heart Palate Hypocalcaemia

Management in Di George syndrome - Children (Nowgen guidelines) • • Heart Palate Hypocalcaemia Immune system • Development and Education • Hearing • Hypothyroidism • Renal • Skeletal www. mangen. co. uk Echocardiogram at diagnosis Examination Check serum calcium levels Arrange lymphocyte count plus T and B cell subsets. Do not give live vaccine until checked. Refer immunology if results abnormal. Developmental assessment Regular hearing checks, monitor S and L TFTs after diagnosis Renal USS after diagnosis Spine xray if evidence of scoliosis.

Management in Di George syndrome - Adults • Baseline investigation: – – – –

Management in Di George syndrome - Adults • Baseline investigation: – – – – Echo Renal USS Calcium, PTH TFTs MRI if evidence of seizures T and B cell subsets, Igs Cognitive assessment • Regular • Ca, PTH • Creat, FBC, TSH • Consider • Autoantibody screen • Fasting glucose and lipid profile • Annual review to include systems review – – Awareness of psychiatric complications Physical exam including BMI Assessment for AI disorders Genetic counselling including prenatal counselling

Case study 2 • 12 month old • Tetralogy of Fallot with PS •

Case study 2 • 12 month old • Tetralogy of Fallot with PS • Mild jaundice • Prominent forehead • Deep set eyes • Pointed chin

Alagille syndrome • JAG 1 (7% microdeletion 20 p 12) • NOTCH 2 (1

Alagille syndrome • JAG 1 (7% microdeletion 20 p 12) • NOTCH 2 (1 -2%) • Bile duct paucity- liver damage (cirrhosis, portal hypertension, liver failure) • CHD esp pulmonary arteries • Growth delay, delayed puberty or FTT • Osteoporosis • Posterior embryotoxon • Dysmorphism • Butterfly vertebrae • Renal dysplasia, RTA, VUR • Very variable, even within families

Management of Alagille syndrome • Multidisciplinary approach • Clinical genetics, gastroenterology, nephrology, nutrition, cardiology,

Management of Alagille syndrome • Multidisciplinary approach • Clinical genetics, gastroenterology, nephrology, nutrition, cardiology, ophthalmology. • Optimize nutrition • Monitor growth • Some associated vascular anomalies- avoid contact sports • Liver transplant for end-stage liver disease • Often have catch up growth post-transplant

Syndromic vs non-syndromic Multifactoral causes • Likely the majority of cases • Recurrence risk

Syndromic vs non-syndromic Multifactoral causes • Likely the majority of cases • Recurrence risk ~3% Genetic causes of To. F Chromosomal • 22 q 11 deletions (Di. George syndrome)- 15% (higher if PA present) • Trisomies - 21 (12%), 13, 18. • Other chromosomal cause eg del 1 q 21 Single gene – syndromic • Alagille syndrome (JAG 1, NOTCH 2) – ~1% • CHARGE syndrome (CHD 7) • Noonan syndrome (PTPN 11 and others) Single gene- non-syndromic (~16% of non-syndromic cases) • JAG 1 • NOTCH 1 (~5%) • VEGFR 3 (~2% cases) (Matos-Nieves et al 2019) • Transcription factors eg TBX 4, NKX 2. 5, GATA 4, HAND 2, GATA 6 (~1%)

 • Genetic testing in TOF Indicated in syndromic cases of To. F –

• Genetic testing in TOF Indicated in syndromic cases of To. F – Other associated problems eg other structural abnormalities, dysmorphic features – Developmental delay – Chromosome analysis by SNP array – Gene testing if features of other diagnosis or family history eg Alagille • Not currently indicated in non-syndromic To. F • ? In recurrence of CHD within a family/ consanguineous family structure • Consider echo for parents of affected child especially if more than one child affected

How to request a genetic test • https: //www. leedsth. nhs. uk/a-z-ofservices/the-leeds-geneticslaboratory/constitutionalgenetics/constitutionalcytogenetics/referral-cards/

How to request a genetic test • https: //www. leedsth. nhs. uk/a-z-ofservices/the-leeds-geneticslaboratory/constitutionalgenetics/constitutionalcytogenetics/referral-cards/

Suggests other management implications eg monitoring calcium/ immune function in 22 q 11 May

Suggests other management implications eg monitoring calcium/ immune function in 22 q 11 May aid in providing prognosis for family Implications of a genetic diagnosis May aid in obtaining funding/ support for child Gives recurrence risk for parents and other family members Gives the option of prenatal testing or PGD

Who to refer to genetics • Positive result for a genetic or syndromic cause

Who to refer to genetics • Positive result for a genetic or syndromic cause • Considering a diagnosis or syndrome of unknown cause • Affected patient considering having children • Complex family history of CHD/ consanguineous family history with recurrence

Counselling patients with To. F planning their own families • Growing prevalence of To.

Counselling patients with To. F planning their own families • Growing prevalence of To. F in adult patients • Empiric recurrence risk in child of patient affected with non-syndromic To. F – Mother affected 2 -5% – Father affected 1 -2% (Burn et al. 1998) • Syndromic forms important to identify as RR could be up to 50% (although phenotypes tend to be variable). • Fetal echo can be offered in pregnancy from 20 weeks.

Variants of Unknown Significance VUS Polymorphism Mutation

Variants of Unknown Significance VUS Polymorphism Mutation

Variations in genes that occur in >1% of the population SNPs (single nucleotide polymorphisms)

Variations in genes that occur in >1% of the population SNPs (single nucleotide polymorphisms) CNVs (copy number variants) Polymorphisms May lead to variation in gene expression May lead to change in protein structure May have no functional effect ? associated with low level increase in cancer risks (esp polygenetic) ? associated with response to treatment/toxicity

Deletions, insertions, substitutions Frameshift – leads to a change in the reading frame of

Deletions, insertions, substitutions Frameshift – leads to a change in the reading frame of amino acids Mutations Nonsense – leads to an early stop codon and truncated protein Missense – changed base leads to a single changed amino acid Splice site – may lead to change in splicing of one or more exons Duplications – duplication of sections of gene e. g. some BRCA mutations

Variants of Unknown Significance VUS Polymorphism Mutation

Variants of Unknown Significance VUS Polymorphism Mutation

Ethics in Genetics • Predictive testing • Outcomes of testing; prenatal diagnosis • Racial

Ethics in Genetics • Predictive testing • Outcomes of testing; prenatal diagnosis • Racial inequality • Consent • Incidental findings • Insurance • WGS and direct-to-consumer testing; consent and identifiable nature of data • Preventative medicine • Historic association of genetics with eugenics • New technologies and gene therapy

That’s all for now folks!

That’s all for now folks!