Genomic copy number alterations in non‐syndromic hearing loss

Abstract

Genetic heterogeneity has made the identification of genes related to hearing impairment a challenge. In the absence of a clear phenotypic aetiology, recurrence risk estimates are often based on family segregation and may be imprecise. We profiled by oligonucleotide array-CGH patients presenting non-syndromic hearing loss with presumptive autosomal recessive (n = 50) or autosomal dominant (n = 50) patterns of inheritance. Rare copy number variants (CNVs) were detected in 12 probands; four of the detected CNVs comprised genes previously associated with hearing loss (POU4F3, EYA4, USH2A, and BCAP31) and were considered causative, stressing the contribution of genomic imbalance to non-syndromic deafness. In six cases, segregation of the CNVs in pedigrees excluded them as causative. In one case, segregation could not be investigated, while in another case, a point mutation likely explains the phenotype. These findings show that the presumptive patterns of inheritance were incorrect in at least two cases, thereby impacting genetic counselling. In addition, we report the first duplication reciprocal to the rare ABCD1, BCAP31, and SLC6A8 contiguous deletion syndrome; as with most microduplication syndromes, the associated phenotype is much milder than the respective microdeletion and, in this case, was restricted to hearing impairment.

BCAP31‐associated encephalopathy and complex movement disorder mimicking mitochondrial encephalopathy

“…A de novo 16 kilo base microduplication at Xq28 encompassing SLC6A8 and BCAP31 has been reported to be associated with a non‐syndromic hearing loss in an individual with consanguine parents (Rosenberg et al, ). There was no detailed clinical information regarding that patient.…”

Aldh inhibitor restores auditory function in a mouse model of human deafness

“…A number of approaches have been taken to identify the disease-causing genes of the DFNA15 deafness, including pedigree and linkage analysis followed by targeted sequencing [3,10,[29][30][31], copy number variation (CNV) analyses [32,33] and more recently whole-exome sequencing [34][35][36][37][38][39]. All these reports point to POU4F3 as the candidate DFNA15 gene in patients that suffer this autosomal dominant progressive hearing loss.…”

A novel missense variant in the nuclear localization signal of POU4F3 causes autosomal dominant non-syndromic hearing loss

“…In 1998, Vahava et al detected an 8-base pair deletion in POU4F3 in a five-generation Israeli Jewish family 4 . To date, only 12 POU4F3 causative variants have been reported in the literature, that is, six missense variants 5 – 10 , five frameshift deletions 4 , 11 – 14 , and a large deletion encompassing the entire gene 15 , 16 . POU4F3 is located on 5q31 and encodes a protein of 338 amino acids, which functions as a transcription factor with two DNA-binding domains: the POU-specific domain and the POU homeodomain 17 .…”