GATA4 Haploinsufficiency in Patients With Interstitial Deletion of Chromosome Region 8p23.1 and Congenital Heart Disease Tugce Pehlivan, 1 Barbara R. Pober, 2,3 Martina Brueckner, 2 Stacey Garrett, 4 Rachel Slaugh, 4 Richard Van Rheeden, 4 David B. Wilson, 4,5 * Michael S. Watson, 4,6 and Anne V. Hing 4 1 Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 2 Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 3 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 4 Departments of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 5 Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 6 Department of Genetics, Washington University School of Medicine, St. Louis, Missouri Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene en- coding GATA-4, a zinc finger transcription factor implicated in cardiac gene expres- sion and development, localizes to chromo- some region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four indi- viduals with del(8)(p23.1) and congenital heart disease were found to be haploinsuffi- cient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth pa- tient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 lo- cus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart dis- ease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 defi- ciency may contribute to the phenotype of patients with monosomy of 8p23.1. Am. J. Med. Genet. 83:201–206, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: chromosome 8p23.1; congeni- tal heart disease; heart devel- opment; transcription factor GATA-4 INTRODUCTION A review of chromosome anomalies found in patients with congenital heart disease suggests that chromo- some region 8p23.1 is a critical locus [Johnson et al., 1997]. Both deletions and inverted duplications at 8p23.1 have been seen in patients with structural heart defects. The first case of an individual with a partial deletion of distal chromosome arm 8p and congenital heart disease was reported in 1973 [Lubs and Lubs, 1973]. Subsequently, there have been over 30 reported cases of 8p deletion, of which 60% have congenital heart disease [Oryee and Craen, 1976; Rodewald et al., 1977; Reiss et al., 1979; Dobyns et al., 1985; Brocker- Vriends et al., 1986; Pecile et al., 1990; Hutchinson et al., 1992; Marino et al., 1992; Wu et al., 1996; Johnson et al., 1997; Digilio et al., 1998]. The cardiac lesions in these cases have included atrioventricular (AV) canal, atrial septal and ventricular septal defects (ASD, VSD), double outlet right ventricle (DORV), dextrocar- dia, pulmonary stenosis (PS), and hypoplastic left heart. Extracardiac findings include minor facial anomalies, mild growth delay, microcephaly, develop- mental delay, behavior problems, genitourinary anomalies, and seizures [Hutchinson et al., 1992]. In this study, we report on five new patients with interstitial deletion of 8p23.1, four of whom have con- Contract grant sponsor: AHA; Contract grant sponsor: NIH; Contract grant number: 9750593 (DBW); Contract grant number: HD36439 (MB); Contract grant number: HL61006 (DBW, MSW, AVH). *Correspondence to: Dr. David B. Wilson, Division of Pediat- rics, Washington University School of Medicine, St. Louis Chil- dren’s Hospital, One Children’s Place, CB 8116, St. Louis, MO 63110. E-mail: wilson_d@kidsa1.wustl.edu Received 8 September 1998; Accepted 4 December 1998 American Journal of Medical Genetics 83:201–206 (1999) © 1999 Wiley-Liss, Inc.