Genetics_in_cardiology_1_per_page_(PDF).pdf

Genetics in Cardiology Rachel Davies Down syndrome • • • • Common defects in Down syndrome Atrioventricular septal defect Ventricular septal defect Atrial septal defect Patent ductus arteriosus Trisomy 21 Which gene(s) cause the problems? Korbel J O et al. PNAS 2009;106:1203112036 DSCA...

Genetics in Cardiology Rachel Davies Down syndrome • • • • Common defects in Down syndrome Atrioventricular septal defect Ventricular septal defect Atrial septal defect Patent ductus arteriosus Trisomy 21 Which gene(s) cause the problems? Korbel J O et al. PNAS 2009;106:1203112036 DSCAM and COL6A2 transgenics • Cell Migration • Cell Adhesion PLOS genetics Grossman et al., 2011 22q11.2 deletion syndrome CATCH-22 • • • • • Cardiac abnormalities Abnormal Facies Thymic aplasia Cleft palate Hypothyroidism Cardiac abnormalities • Interruption of aortic arch • Tetralogy of Fallot • Ventricular septal defect 22q11.2 deletion syndrome (DiGeorge Syndrome) Why do deletions arise? DiGeorge syndrome without deletion The Lancet Volume 362, Issue 9393 (2003) p1366 - 1373 Mutations in TBX1 The Lancet Volume 362, Issue 9393 (2003) p1366 - 1373 TBX-1 Transcription factor Dose dependent phenotype 4th pharyngeal arch arteries +/+ +/- Transgenic, 5xnormal -/- Liao J et al. Hum. Mol. Genet. 2004;13:1577-1585 Model Liao J et al. Hum. Mol. Genet. 2004;13:1577-1585 Long QT • Exceed 99th percentile values What mode of inheritance? Zhang et al., Eur J of Paediatrics 2007 v166 p927-33 Delays in repolarisation Channelopathy * * * * Mutations in these genes account for 60-70% of long QT- locus heterogeneity Loss of function mutations Different mutations in the same gene can cause the same disease- allelic heterogeneity Gain of function mutations • SCN5A Na+ channel stays open Why is it important to identify mutation? Risk for life-threatening cardiac events by mutation location and β-blocker treatment. Barsheshet A et al. Circulation 2012;125:1988-1996 Familial Hypercholesterolemia • High concentration of serum LDL cholesterol (total cholesterol>7.5mM) • Xanthoma • Atherosclerosis Simon Broome criteria Definite FH Possible FH Cholesterol >6.7mM (LDL>4mM) in children under 16 OR >7.5mM (LDL>4.9mM) in adults PLUS either PLUS either Tendon xanthoma in patient or 1st/2nd degree relative Family history of myocardial infarction <50 years in 2nd degree relative or <60 years in 1st degree relative OR OR DNA confirmation Family history of cholesterol >7.5mM in 1st/2nd degree relative Autosomal Dominant Compound heterozygote Which gene(s)? Mutations in LDL-receptor pathway • LDL receptor >1000 different mutations – Not synthesised – Not transported properly to cell membrane – Not bind LDL properly – Not internalised properly – Not recycled properly • ApoB - Arg3500Gln • LDL receptor associated protein - null mutations • PCSK9 - Asp374Tyr Can this disorder be treated? Versmissen J et al. BMJ 2008;337:bmj.a2423 Inclisirin harnesses a natural process Changes in LDL Cholesterol Levels Ray KK et al. N Engl J Med 2017;376:1430-1440 Cascade testing Summary • • • • • • • Effects of gene dosage Autosomal dominant/recessive Locus heterogeneity Allelic heterogeneity Compound heterozygosity Penetrance Cascade testing vs population screening