Familial syndromic esophageal atresia maps to 2p23-p24

Abstract

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 (approximately 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.

Figure 1

Pedigrees used in the DNA-marker studies. Segregation of chromosome 2 markers is seen in the three-generation Dutch family with ODED syndrome (family A). The blackened bar indicates the haplotype that segregates with the disease. Affected patients III:5 and III:7 show recombination at markers D2S352 and D2S131, respectively. Pedigrees of the two smaller families with ODED syndrome (families B and C) confirm linkage to the 2p23-p24 region. A recombination at D2S390 in individual II:3 (family C) defines the proximal border of the linkage interval.

Figure 2

CA-repeat analysis of the microdeletion in 2p23-p24 in family D with ODED syndrome. In this family, the genotypes in the affected mother and daughter are inconsistent with Mendelian inheritance for the markers between D2S2199 and D2S320. In the affected daughter, these markers show only the father’s allele and not the allele that is present in the mother. The mother is also hemizygous for these markers. Note that marker D2S2267 is either homozygous or hemizygous in individual II:1.

Figure 3

FISH characterization of the microdeletion in 2p23-p24 in family D with ODED syndrome. FISH with YAC probe 953G11 from 2p23-p24 shows only a single signal in a patient with ODED syndrome (patient II:1 in family D).

Figure 4

Pedigree of family E with nonsyndromic familial EA. Marker D2S149 segregates with the nonsyndromic form of familial EA. A recombination in individual IV-1 excludes markers proximal to D2S144.

Figure 5

Human SIX2 partial cDNA sequence. Primers used are in italic lowercase type; start and stop codons are in boldface type; the SIX domain is underlined; and the homeobox domain is underlined twice.

Figure 6

Comparison of linkage intervals for families A–C with ODED syndrome, the microdeletion in family D (the diagonally barred area indicates possible reduction of the deleted area; see text), and the cosegregating haplotype in nonsyndromic family E. In family E, the linkage interval continues more distally. Distances (in cM) between each marker and the next are indicated and are computed on the basis of average distances on the Généthon map for chromosome 2 (Dib et al. 1996).