Why did this happen? Genetic and teratologic considerations in CHD Jennifer Kussmann, MS,CGC. The Children's Mercy Hospital, 2014.

Transcription

1 Why did this happen? Genetic and teratologic considerations in CHD Jennifer Kussmann, MS,CGC The Children's Mercy Hospital, /14

2 Risk factors Family history Maternal medical condition/ illness Monochorionic twinning Maternal exposure Noncardiac anomalies Genetic syndrome

3 Things to consider Isolated CHD or syndromic? Cannot rule out a syndrome until the baby is born Vision/hearing Development/tone/neurologic function Dysmorphic features Familial CHD can be isolated or syndromic Syndromes often present differently in different people Genetic syndromes are often not inherited

4 Family history of isolated CHD Population incidence 0.5 Sibling of isolated case 2-3 Half sibs/2 nd degree relatives 1-2 Offspring of isolated case: Father 2-3 Mother 5-6 Two affected sibs (or sib + parent) 10 More than two affected 1 st degree relatives Risk varies with specific diagnosis RISK (%) Harper (2004). Practical Genetic Counseling sixth edition. 50 (approx.)

5 Maternal conditions Condition Heart defect Relative risk Absolute risk Diabetes Any cardiac defect 5 3-5% heterotaxy 6.2 truncus arteriosus 4.72 dtga 2.85 single ventricle defect Lupus/ Sjogrens complete heart block (CHB) 1-5 % previous affect child- CHB 11-19% Infection Any defect % IVF and/or ICSI ASD, VSD 1-3% Monochorionic twins TTTS and/or ASD % Diagnosis and Treatment of Fetal Cardiac Disease A Scientific Statement From the American Heart Association. Circulation. 2014;129:00-00.

6 Exposures Exposure Heart defect Relative risk Absolute risk Anticonvulsants Any defect % Lithium Any defect 1.1 Ibuprofen Any defect % Ductal constriction 5-50% SSRIs Any defect % Marijuana VSD 1.9 Ebstein s 2.4 Good resources for exposures: Organization of Teratology Information Specialists: REPROTOX : Diagnosis and Treatment of Fetal Cardiac Disease A Scientific Statement From the American Heart Association. Circulation. 2014;129:00-00.

7 Fetal anomalies 25-45% of fetuses with 1 anomaly have a CHD Defect Risk for CHD Omphalocele 30% Duodenal atresia 20% CDH 30% CNS malformation 5-15% GU malformation 71% Diagnosis and Treatment of Fetal Cardiac Disease A Scientific Statement From the American Heart Association. Circulation. 2014;129:00-00.

8 Is it genetic? Genetic vs inherited Majority have a fam hx neg for CHD >1 difference = suspicion for a syndrome Growth AF level Anomalies Certain anomalies more likely syndromic Most genetic syndromes cannot be diagnosed with karyotype or chromosomal microarray POSTNATAL evaluation/counseling is important

9 Genetic Testing Wimalasundera, Congenital heart disease and aneuploidy Prenat Diagn 2004; 24:

10 Connor, Genetic Testing Practices in Infants with Congenital Heart Disease. Congenit Heart Dis Mar-Apr;9(2):158-67

11 Genetic testing Normal Karyotype 75% -85% with isolated cardiac malformation 25% to 65% with additional extracardiac Isolated Cardiac defect detection rates Connor, Genetic Testing Practices in Infants with Congenital Heart Disease. Congenit Heart Dis Mar-Apr;9(2): Diagnosis and Treatment of Fetal Cardiac Disease A Scientific Statement From the American Heart Association. Circulation. 2014;129:00-00.

12 Should we order a microaray? This study excluded all babies with abnormal karytoypes Liao, Prenatal diagnosis of congenital heart defect by genome-wide high-resolution SNP array. Prenat Diagn Apr 9

13 Common Genetic Syndromes Syndrome Usual Heart defects Other US anomalies Sib Recurrence risk Turner CoAo, HLHS cystic hygroma, renal <1% Down Trisomy 21 AVSD, ASD, VSD, TOF NT, duodenal atresia, renal, shorten long bones 1% or maternal age risk Trisomy 18 VSD, ASD, varied IUGR, CNS, renal, omphalocele, polyhydramnios, clenched fists 1% or maternal age risk Trisomy 13 VSD, ASD, varied polydactyly, CNS, clefts, renal, omphalocele 1% or maternal age risk Williams SVAS, PPS IUGR Low if de novo Low if de novo, 22q deletion conotruncal, VSD cleft palate, renal 50% if inherited Miller-Dieker TOF, VSD IUGR, lissencephaly Low if de novo Rubenstein-Taybi VSD, PDA renal Low if de novo Noonan PVS, HCM cystic hygroma, polyhydramnios PTPN11, multiple genes Holt Oram ASD, VSD upper limb defects TBX5 Alagille TOF, PPS renal JAG1, NOTCH2 Ellis Van Creveld ASD, AVSD dwarfism, clefts, polydactyly EVC, EVC2 Primary ciliary dyskinesia Tuberous sclerosis rhabdomyoma, arrhythmias dextrocardia situs inversus ZIC3, multiple genes subependymal nodules, hydrops, renal TSC1, TSC2

14 References Fahed, Genetics of congenital heart disease: the glass half empty. Circ Res. 2013;112: Connor, Genetic Testing Practices in Infants with Congenital Heart Disease. Congenit Heart Dis Mar- Apr;9(2): Wimalasundera, Congenital heart disease and aneuploidy Prenat Diagn 2004; 24: Liao, Prenatal diagnosis of congenital heart defect by genome-wide high-resolution SNP array. Prenat Diagn Apr 9 Diagnosis and Treatment of Fetal Cardiac Disease A Scientific Statement From the American Heart Association. Circulation. 2014;129: Greenwood, Extracardiac abnormalities in infants with congenital heart disease. Pediatrics. 1975;55: Gallo P, Congenital extracardial malformations accompanying congenital heart disease. G Ital Cardiol. 1976;6: Wallgren, Extracardiac malformations associated with congenital heart disease. Eur J Cardiol. 1978;7: Miller A, Congenital heart defects and major structural noncardiac anomalies, Atlanta, Georgia, 1968 to J Pediatr. 2011;159:70 78.e2.