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 (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.
Celli
J
J
Human Genetics, University Hospital Nijmegen, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands. j.celli@antrg.azn.nl
van Beusekom
E
E
Hennekam
R C
RC
Gallardo
M E
ME
Smeets
D F
DF
de Córdoba
S R
SR
Innis
J W
JW
Frydman
M
M
König
R
R
Kingston
H
H
Tolmie
J
J
Govaerts
L C
LC
van Bokhoven
H
H
Brunner
H G
HG
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003001:Cloning, Molecular; D004933:Esophageal Atresia / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008126:Lod Score; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D009426:Netherlands; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion / Q000235:genetics; D013577:Syndrome
D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C484762:SIX2 protein, human