Familial syndromic esophageal atresia maps to 2p23-p24

Esophageal atresia (EA) is a common life-threatening congenital anomaly tha t occurs in 1/3,000 newborns. Little is known of the genetic factors that u nderlie EA. Oculodigitoesophageoduodenal (ODED) syndrome (also known as "Fe ingold syndrome") is a rare autosomal dominant disorder with digital abnorm alities, microcephaly, short palpebral fissures, mild learning disability, and esophageal/duodenal atresia. We studied four pedigrees, including a thr ee-generation Dutch family with 11 affected members. Linkage analysis was i nitially aimed at chromosomal regions harboring candidate genes for this di sorder. Twelve different genomic regions covering 15 candidate genes (simil ar to 15% of the genome) were excluded from involvement in the ODED syndrom e, A subsequent nondirective mapping approach revealed evidence for linkage between the syndrome and marker D2S390 (maximum LOD score 4.51 at recombin ation fraction 0). A submicroscopic deletion in a fourth family with ODED p rovided independent confirmation of this genetic localization and narrowed the critical region to 7.3 cM in the 2p23-p24 region. These results show th at haploinsufficiency for a gene or genes in 2p23-p24 is associated with sy ndromic EA.