Description of a large kindred with autosomal dominant inheritance of branchial arch anomalies, hearing loss, and ear pits, and exclusion of the branchio-oto-renal (BOR) syndrome gene locus (chromosome 8q13.3)

Abstract

It has been suggested that branchio-oculo-facial (BOF) syndrome, deafness with ear pits, and associated conditions [MIM nos. 125100, 120502], and branchio-oto-renal (BOR) [MIM no. 113650] or Melnick-Fraser syndrome represent phenotypic variants of the BOR syndrome, which is inherited in an autosomal dominant (AD) manner and has variable clinical expression. Recently, the BOR gene was mapped to chromosome region 8q13.3 and its sequence was identified as the human homolog of the Drosophila eyes absent (EYA1) gene. We studied an extended family with AD inheritance 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 stenosis. Fifteen affected members were studied; ear pits were present in all of them, whereas hearing loss and other BAA were present in 40 and 20%, respectively. Blood was collected from 31 patients; DNA was extracted by standard methods and amplified using primers from microsatellite sequences flanking the BOR locus on chromosome 8q13.3 (D8S1807, D8S530, and D8S543). Linkage analysis was performed under two models of AD inheritance with different penetrance: 100% and 80%. In both cases, the logarithm of odds (LOD) scores produced were significantly less than -2; exclusion of the 8q13.3 locus was also confirmed by multipoint LOD score analysis. We conclude that, in one large family with AD inheritance 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.

Investigation of a patient with a partial trisomy 16q including the fat mass and obesity associated gene (FTO): Fine mapping and FTO gene expression study

“…Genomic DNA was extracted from peripheral blood as previously described [Stratakis et al, 1998]. We used a pool of genomic DNA from 18 healthy female VUmc locals as a reference.…”

Genomewide Search and Genetic Localization of a Second Gene Associated with Autosomal Dominant Branchio-Oto-Renal Syndrome: Clinical and Genetic Implications

“…However, identification of the second gene will help resolve this issue. Given the fact that the BOR syndrome phenotype is highly heterogeneous and that other families with BO have been shown not to have linkage to the 8q region (Stratakis et al 1998), it is possible that there is a third responsible locus in branchiogenic disorders.…”

Genetic heterogeneity associated with branchio-oto-renal syndrome

“…It is possible that most mutations lie in the noncoding region of the gene or that another gene is involved. A recent report of different linkages [not 8q] with BO-like [Kumar et al, 1998a] disorders [Stratakis et al, 1998] gives credence to the involvement of other genes associated with combined branchial and ear anomalies. The clinical phenotype reported in our BO paper [Kumar et al, 1998a] is consistent with many of our BO families that showed mutation in the EYA1 gene with the exception of the presence of commissural lip pits.…”