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Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome

Abstract

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchiogenic anomalies, hearing loss, and renal anomalies. The aim of this study was to reveal the clinical phenotypes and their causative genes in Japanese BOR patients. Patients clinically diagnosed with BOR syndrome were analyzed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA), array-based comparative genomic hybridization (aCGH), and next-generation sequencing (NGS). We identified the causative genes in 38/51 patients from 26/36 families; EYA1 aberrations were identified in 22 families, SALL1 mutations were identified in two families, and SIX1 mutations and a 22q partial tetrasomy were identified in one family each. All patients identified with causative genes suffered from hearing loss. Second branchial arch anomalies, including a cervical fistula or cyst, preauricular pits, and renal anomalies, were frequently identified (>60%) in patients with EYA1 aberrations. Renal hypodysplasia or unknown-cause renal insufficiency was identified in more than half of patients with EYA1 aberrations. Even within the same family, renal phenotypes often varied substantially. In addition to direct sequencing, MLPA and NGS were useful for the genetic analysis of BOR patients.

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Acknowledgements

We thank all the participants and their families. We also thank Takashi Sekine (Toho University), Yoshitsugu Kaku, Pin Fee Chong (Fukuoka Children’s Hospital), Ayu Ogawa (Okayama University), Seiji Tanaka (Kurume University), Tsukasa Takemura (Kindai University), Kotaro Nomura (St Luke’s International Hospital), Midori Awazu (Keio University), Kazuaki Matsumoto (JA Toride Medical Center), Takahisa Yoshikawa (Kyoto University), Chikahiko Numakura (Yamagata University), Kei Nishiyama (Kyushu University), and Toshihiko Shirakawa (Nagasaki University) for their contributions. Furthermore, we are profoundly grateful to Tetsuko Yamanouchi and Yoshimi Nozu (Kobe University) for their technical assistance. We would like to thank Editage (www.editage.jp) for English language editing.

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Correspondence to Naoya Morisada.

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This work was supported by a Health Labor Sciences Research Grant for the Research on Measures for Intractable Diseases (H21-nanchi-ippan-103 to K.I., H24-nanchi-ippan-041 to K.I., and H29-nanchi-ippan-039 to N.M.) and Japan Society for the Promotion of Science KAKENHI grant number JP15K09261 (to N.M.). The authors declare that they have no conflict of interest.

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Unzaki, A., Morisada, N., Nozu, K. et al. Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome. J Hum Genet 63, 647–656 (2018). https://doi.org/10.1038/s10038-018-0429-8

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