Coincidental or disease-relevant disruption of the ATE1 and SLC12A1 genes by balanced translocation t(10;15)(q26.13;q21.1) in a boy with non-syndromic hearing loss

Background: Positional cloning of disease-associated chromosome rearrangments is a promising strategy for the identification of disease genes. We report on a boy with nonsyndromic hearing loss and an apparently balanced translocation t(10;15)(q26.13;q21.1). The same translocation was found in the normally hearing father and brother of the index patient; however, this does not exclude its involvement in disease pathogenesis, for example by unmasking a recessive mutation. Methods: The breakpoint regions were narrowed down via FISH with BAC clones and longrange PCR products. In addition, microarray analysis and targeted sequencing of a deafness gene panel was performed in the index patient. Mutation analysis of two genes disrupted by translocation was performed in a cohort of patients with congenital hearing impairment. Expression patterns were studied by RNA in situ hybridization in zebrafish embryos. Results: The translocation disrupts the arginyltransferase 1 (ATE1) gene on the derivative chromosome 10 and the solute carrier family 12, member 1 gene (SLC12A1) on the derivative chromosome 15. SNP-array analysis revealed neither loss nor gain of chromosomal regions in the affected child and a targeted gene enrichment panel consisting of 130 known deafness genes was negative for pathogenic mutations. The expression patterns in zebrafish and humans do not provide evidence for ear-specific functions of the ATE1 and SLC12A1 genes. Sanger sequencing of the two genes in the index patient and 180 GJB2 mutation-negative hearing loss patients did not detect homozygous or compound heterozygous pathogenic mutations.