DESCRIPTION OF A LARGE KINDRED WITH AUTOSOMAL-DOMINANT INHERITANCE OFBRANCHIAL ARCH ANOMALIES, HEARING-LOSS, AND EAR PITS, AND EXCLUSION OF THE BRANCHIOOTORENAL (BOR) SYNDROME GENE LOCUS (CHROMOSOME 8Q13.3)

It has been suggested that branchio-oculo-facial (BOF) syndrome, deafn ess with ear pits, and associated conditions [MIM nos. 125100, 120502] , and branchio-oto-renal (BOR) [MIM no. 113650] or Melnick-Fraser synd rome represent phenotypic variants of the BOR syndrome, which is inher ited in an autosomal dominant (AD) manner and has variable clinical ex pression. Recently, the BOR gene was mapped to chromosome region 8q13. 3 and its sequence was identified as the human homolog of the Drosophi la eyes absent (EYA1) gene. We studied an extended family with AD inhe ritance of branchial arch anomalies (BAA), hearing loss, and ear pits, whose phenotype differed from that of patients with BOR in that none of the affected members had renal abnormalities or lacrimal duct steno sis, Fifteen affected members were studied; ear pits were present in a ll of them, whereas hearing loss and other BAA mere present in 40 and 20%, respectively, Blood was collected from 31 patients; DNA was extra cted by standard methods and amplified using primers from microsatelli te sequences flanking the BOR locus on chromosome 8q13.3 (D8S1807, D8S 530, and D8S543). Linkage analysis was performed under two models of A D inheritance with different penetrance: 100% and 80%, In both cases, the logarithm of odds (LOD) scores produced were significantly less th an -2; exclusion of the 8q13.3 locus was also confirmed by multipoint LOD score analysis. We conclude that, in one large family with AD inhe ritance of BAA, hearing loss and ear pits, the BOR locus was excluded. This represents the first documentation of heterogeneity in branchio- oto anomalies, syndromes with phenotypes similar to BOR syndrome. (C) 1998 Wiley-Liss, Inc.