Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family

Abstract

Objective: To identify novel genetic causes of syndromic hearing loss in Brazil. Design: To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. Study sample: Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. Results: Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. Conclusions: Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.

Key Words::

• Syndromic deafness
• ear malformation
• array-CGH
• genetic mapping
• copy number variation (CNV)

Acknowledgements

We thank Maria Teresa Balester de Mello Auricchio (Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, Brazil) for technical assistance. We thank Maria Cristina C. Braga Scorzafave (from Departamento de Biotecnologia, Genética e Biologia Celular, Universidade Estadual de Maringá), for helping with collection of genetic data and samples. We also thank Dr. Jeferson Cedaro de Mendonça for his analysis of CT scanning and Dr. Sergio Seiji Yamada for interpretation of tests of renal function, both from the Department of Medicine, Universidade Estadual de Maringá. We thank FAPESP (process 2003/04780-9, 2009/00898-1 and 2009/05620-1), CEPID-FAPESP Human Genome and Stem Cell Research Center (HGRC- FAPESP/CEPID process 98/14254-2, Coordinator: Mayana Zatz) and CAPES for financial support. This study was presented as an abstract at the following scientific meeting: Mingroni-Netto, Regina Célia, Dantas VGL, Freitas EL, Moraes AMM, Braga MCC, Ramos SB, Rosenberg C, Della-Rosa VA. Duplication of EYA1 causes branchiootic syndrome in a Brazilian family. American Society of Human Genetics 2013 Annual Meeting, 2013. p.2938F–2938F.

Declaration of interest: The authors declare no conflicts of interest.