Familial syndromic esophageal atresia maps to 2p23-p24

Esophageal atresia (EA) is a common life-threatening congenital anomaly that occurs in 1/3,000 newborns. Little is known of the genetic factors that underlie EA. Oculodigitoesophageoduodenal (ODED) syndrome (also known as 'Feingold syndrome') is a rare autosomal dominant disorder with digital abnormalities, microcephaly, short palpebral fissures, mild learning disability, and esophageal/duodenal atresia. We studied four pedigrees, including a three-generation Dutch family with 11 affected members. Linkage analysis was initially aimed at chromosomal regions harboring candidate genes for this disorder. Twelve different genomic regions covering 15 candidate genes (~15% of the genome) were excluded from involvement in the ODED syndrome. A subsequent nondirective mapping approach revealed evidence for linkage between the syndrome and marker D2S390 (maximum LOD score 4.51 at recombination fraction 0). A submicroscopic deletion in a fourth family with ODED provided independent confirmation of this genetic localization and narrowed the critical region to 7.3 cM in the 2p23-p24 region. These results show that haploinsufficiency for a gene or genes in 2p23-p24 is associated with syndromic EA.

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