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(Circulation. 2000;102:432.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Deletion of a 5-cM Region at Chromosome 8p23 Is Associated With a Spectrum of Congenital Heart Defects

Sabrina Giglio, MD; Sharon L. Graw, PhD; Giorgio Gimelli, PhD; Barbara Pirola, PhD; Paolo Varone, PhD; Lucille Voullaire, MSc; Franco Lerzo, MD; Elena Rossi, PhD; Claudia Dellavecchia, PhD; Maria Clara Bonaglia, PhD; Maria Cristina Digilio, MD; Aldo Giannotti, MD; Bruno Marino, MD; Romeo Carrozzo, MD; Julie R. Korenberg, MD; Cesare Danesino, MD; Eva Sujansky, MD; Bruno Dallapiccola, MD; Orsetta Zuffardi, PhD

From the Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy (S.G., B.P., E.R., C. Dellavecchia, C. Danesino, O.Z.); the Eleanor Roosevelt Institute, Denver, Co (S.L.G.); the Laboratorio di Citogenetica and Divisione di Cardiochirurgia, Istituto G. Gaslini, Genova, Italy (G.G., P.V., F.L.); the Murdoch Institute, Royal Children’s Hospital, Parkville, Australia (L.V.); the Istituto Scientifico E. Medea, Bosisio Parini, Lecco, Italy (M.C.B); the Genetica Medica e Cardiologia, Ospedale Bambin Gesù, Rome, Italy (M.C.D., A.G., B.M.); Medical Genetics Division, Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, Calif (J.R.K.); University of Colorado Health Sciences Center, Denver, Co (E.S.); the University La Sapienza and Istituto CSS-Mendel, Rome, Italy (B.D); and the Ospedale San Raffaele, Milan, Italy (R.C., O.Z.).

Background—Cytogenetic evidence suggests that the haploinsufficiency of 1 gene located in 8p23 behaves as a dominant mutation, impairing heart differentiation and leading to a wide spectrum of congenital heart defects (CHDs), including conotruncal lesions, atrial septal defects, atrioventricular canal defects, and pulmonary valve stenosis. An 8p heart-defect–critical region was delineated, and the zinc finger transcription factor GATA4 was considered a likely candidate for these defects. We narrowed this region and excluded a major role of GATA4 in these CHDs.

Methods and Results—We studied 12 patients (7 had CHD and 5 did not) with distal 8p deletions from 9 families by defining their chromosome rearrangements at the molecular level by fluorescent in situ hybridization and short-tandem repeat analysis. Subjects with 8p deletions distal to D8S1706, at 10 cM from the 8p telomere, did not have CHD, whereas subjects with a deletion that included the more proximal region suffered from the spectrum of heart defects reported in patients with 8p distal deletions. The 5-cM critical region is flanked distally by D8S1706 and WI-8327, both at 10 cM, and proximally by D8S1825, at 15 cM. Neither GATA4 nor angiopoietin-2 (ANGPT2; a gene in 8p23 involved in blood vessel formation) were found to be deleted in some of the critical patients. We also found that CHDs are not related to the parental origin of deletion.

Conclusions—Haploinsufficiency for a gene between WI-8327 and D8S1825 is critical for heart development. A causal relationship does not seem to exist between GATA4 and ANGPT2 haploinsufficiency and CHDs.

Key Words: heart defects, congenital • chromosomes, 8 • gene deletion • GATA4 • ANGPT2

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