Mutations in GATA4, NKX2.5, CRELD1, and BMP4 are infrequently found in patients with congenital cardiac septal defects

Cardiac septal defects constitute the majority ofcongenitalheartdisease(CHD)inhumansandfamilialrecurrenceisreportedtoexceed5%[Burnetal.,1998].Previously, mutations in GATA4 and NKX2.5 havebeendescribedtobepathogenicforostiumsecundumatrial septal defects (ASDII) and ventricular septaldefects(VSD)[Schottetal.,1998;Gargetal.,2003].Incontrast, CRELD1 and BMP4 constitute functionalcandidatesforregulardevelopmentoftheendocardialcushionandmutationsinthesegenescause atrioven-tricular septal defects (AVSD) in animal models andhumans [Jiao et al., 2003; Robinson et al., 2003]. Wehypothesizedthatmutationsin GATA4(NM_002052),NKX2.5 (NM_004387), CRELD1 (NM_015513), andBMP4(NM_001202)canbeidentifiedinalargecohortof patients withcongenital septal defects with a focusonASDII.Weanalyzedthecodingregionofthesefourgenesin205patientswithcongenitalseptaldefectsbysinglestrandedconformationalpolymorphism(SSCP)and sequencing. The patient cohort was assembledout of 110 patients with isolated ASDII. Of these,four subjects (3.6%) mentioned a familial history andformal segregation analysis of pedigrees suggestedan autosomal dominant inheritance. However, familyrelatives were not studied systematically. To thishomogenous ASDII patient cohort we added agroupof95individualswithdifferentcongenitalseptaldefects (60 ASDII, 22 perimembranous VSD, and13 AVSD) and concomitant minor cardiac malforma-tions (Aortic coarctation ¼CoA, persistent ductusarteriosus¼PDA or partial anomalous venousreturn¼PAPVR). These patients were included as asubgroup in a candidate gene approach reportedpreviously [Ozcelik et al., 2006]. All patients wereattending the Department for Congenital Heart Dis-ease, German Heart Institute Berlin (GHIB). Patientswith syndromic appearance and/or limb malforma-tions were excluded from the genetic study andcontrolsubjectswerematchedforethnicity.Thestudyprotocol was approved by the Institutional ReviewBoard of the GHIB and Charite´.A heterozygous c.1750C>T mutation of GATA4,which predicts p.A411V, was identified in a cauca-sian patient with multiperforated ASDII and PAPVR.After exclusion in 600 control chromosomes weconsideredthevarianttobeanovelASDIIassociatedmutation representing the fifth GATA4 mutationidentified in a patient with ASDII. The carrier was a73-year-old female with ASDII and sustained atrial

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