Abstract
The branchio–oto–renal (BOR) syndrome is an autosomal-dominant disorder characterized by hearing loss, branchial and renal anomalies. BOR is genetically heterogeneous and caused by mutations in EYA1 (8q13.3), SIX1 (14q23.1), SIX5 (19q13.3) and in an unidentified gene on 1q31. We examined six Danish families with BOR syndrome by assessing linkage to BOR loci, by performing EYA1 multiplex ligation-dependent probe amplification (MLPA) analysis for deletions and duplications and by sequencing of EYA1, SIX1 and SIX5. We identified four EYA1 mutations (c.920delG, IVS10−1G>A, IVS12+4A>G and p.Y591X) and one SIX1 mutation (p.W122R), providing a molecular diagnosis in five out of the six families (83%). The present, yet preliminary, observation that renal and temporal bone malformations are less frequent in SIX1-related disease suggests a slightly different clinical profile compared to EYA1-related disease. Unidentified mutations impairing mRNA expression or further genetic heterogeneity may explain the lack of mutation finding in one family despite LOD score indications of EYA1 involvement.
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Acknowledgements
We thank the families who participated in this study. In addition, we acknowledge the skilful guidance and technical assistance of Annemette Friis Mikkelsen, Lillian Egebjerg Rasmussen and Karen Friis Henriksen, and valuable technical help from Elvira Chapka and Marianne Lodahl at Department of Cellular and Molecular Medicine, ICMM, The Panum Institute. We also thank laboratory technician Anne-Lise Palle at the University Hospital, Rigshospitalet, Copenhagen, for performing the MLPA analysis, and Stephanie Fischer and Richard Smith, Department of Otolaryngology Head and Neck Surgery, University of Iowa Medical School, Iowa City, USA, for providing control samples for the MLPA analysis. The project was hosted by Wilhelm Johannsen Centre for Functional Genome Research, which is funded by the Danish National Research Foundation. The study was supported by the Oticon Foundation and Widex AS (NDR, LT and KMS).
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Sanggaard, K., Rendtorff, N., Kjaer, K. et al. Branchio–oto–renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses. Eur J Hum Genet 15, 1121–1131 (2007). https://doi.org/10.1038/sj.ejhg.5201900
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DOI: https://doi.org/10.1038/sj.ejhg.5201900
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