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Abstract Objective Hereditary hearing loss is the most common neurosensory disorder in humans caused by myriad mutations in numerous genes. Autosomal recessive nonsyndromic hearing loss (ARNSHL) accounts for 80% of hearing impairments of genetic origin and is quite prevalent in societies with a high rate of consanguinity. In the current study, we investigated the causes of sensorineural hearing loss in 24 unrelated Iranian families who were mainly consanguineous and had at least two affected children. Methods All probands were initially screened for GJB2 mutations, as the most common causes of ARNSHL in Iran. Verified GJB2-negative samples were subsequently subjected to whole exome sequencing (WES) to identify the underlying causes of hearing impairment, and the variants identified in each family were further confirmed by Sanger sequencing. Results WES revealed three previously unreported mutations in MYO15A, the gene encoding the unconventional myosin 15 (Myo15). All variants identified, c.C6436T (p.R2146W), c.C9584G (p.P3195R) and c.G10266C (p.Q3422H), reside in the MYTH4 (myosin tail homology) and FERM (4.1 ezrin, radixin, moesin) domains of the protein. Conclusion Globally, mutations in MYO15A are considered to be among the most prevalent genetic causes of ARNSHL, and they rank as the third leading cause of hearing loss in the Iranian population, below GJB2 and SLC26A4. Yet again, these results endorse the importance of MYO15 screening in hearing impaired populations, particularly in Iran. [ABSTRACT FROM AUTHOR]

Objectives Autosomal recessive non-syndromic hearing loss is a heterogeneous disorder and the most prevalent human genetic sensorineural defect. In this study, we investigated the geneticcause of sensorineural hearing loss in Moroccan patients and presented the importance of whole exome sequencing (WES) to identify candidate genes in two Moroccan families with profound deafness. Methods After excluding mutations previously reported in Moroccan deaf patients, whole exome sequencing was performed and Sanger sequencing was used to validate mutations in these genes. Results Our results disclosed the c.113_114insT (p.Lys41GlufsX8) and c.406C > T (p.Arg130X) homozygous mutations in PJVK and a homozygous c.5203C > T (p.Arg1735Trp) mutation in MYO15A , both genes responsible for non-syndromic recessive hearing loss DFNB59 and DFNB3, respectively. Conclusion We identified in Moroccan deaf patients two mutations in PJVK and one mutation in MYO15A described for the first time in association with non-syndromic recessive hearing loss. These results emphasize that whole exome sequencing is a powerful diagnostic strategy to identify pathogenic mutations in heterogeneous disorders with many various causative genes. [ABSTRACT FROM AUTHOR]

Sensorineural hearing loss (SNHL) is the most prevalent genetic sensory defect in humans, affecting about 1 in 1000 newborns around the world. Non-syndromic SNHL accounts for nearly 70% of hereditary hearing loss and 80% of SNHL cases show an autosomal recessive mode of inheritance (ARNSHL). In the present study, we applied targeted-exome sequencing to a family with a single proband affected by congenital sensorineural hearing loss. 127 known genes were sequenced to find the causative mutation. One novel homozygous donor splice site mutation, c.4596 + 1G > A (IVS12 + 1G > A) was found in MYO15A gene. Analysis of this mutation within the family showed that the mutation segregates with hearing loss. New DNA sequencing technologies could lead to identification of the disease causing variants especially in highly heterogeneous disorders such as hearing loss. [ABSTRACT FROM AUTHOR]

Hearing loss (HL) is one of the most common human defects which affects millions of people globally. The identification of deafness-related genes or loci may facilitate basic and clinical translational research on this disorder. Here, we investigated a Chinese family with autosomal recessive non-syndromic hearing impairment. Using targeted massively parallel sequencing, we identified a novel homozygous mutation, c.3525_3526insA and p.Q1175fsX1188 (NM_016239), in exon 2 of MYO15A . Sanger sequencing confirmed that affected siblings were homozygous for the mutation, whereas both normal hearing parents were heterozygous. The mutation was absent in 96 healthy controls and public databases. The insertion leads to a frameshift and a truncated form of the protein, resulting in the pathogenic effect of hearing loss for the patients. Mutations in exon 2 of MYO15A may cause a less severe phenotype, facilitating the rapid identification of mutations in exon 2 among the 66 exons when linkage of less severe hearing loss to Deafness, Autosomal Recessive 3 (DFNB3) is detected. Our data provide additional molecular information for establishing a better genotype–phenotype understanding of DFNB3. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in MYO15A are associated with deafness in humans, and shaker 2 mice also exhibit a hearing loss due to defects of unconventional myosin 15a. We ascertained a consanguineous Pakistani family with recessively inherited moderate to severe hearing loss, which putatively segregated with markers linked to the DFNB3 locus. Prioritized sequencing of the second exon of MYO15A from the DNA of all affected individuals of family revealed a duplication of Cytosine in a stretch of seven repetitive C nucleotides (c.1185dupC). This mutation results in a frameshift and incorporates a stop codon in the open reading frame of MYO15A (p.E396fsX431). The findings of less severe hearing loss in families with linkage to DFNB3 are only reported for some individuals with mutations in exon 2 of MYO15A, which are further supported by this study. Therefore, on basis of linkage data and the presence of a less severe hearing loss phenotype, sequencing of a single exon of MYO15A can efficiently identify the causative mutations in patients from these families. [Copyright &y& Elsevier]

• Variants in MYO15A causing DFNB3 lead to audiological heterogeneity. • N-terminal truncating variants in MYO15A showed significant residual hearing. • Missense variants in the second FERM domain showed better low frequency hearing. • Such variants allow acoustic stimulation with hearing aids and cochlear implants. Autosomal recessive nonsyndromic hearing loss 3 (DFNB3) mainly leads to congenital and severe-to-profound hearing impairment, which is caused by variants in MYO15A. However, audiological heterogeneity in patients with DFNB3 hinders precision medicine in hearing rehabilitation. Here, we aimed to elucidate the heterogeneity of the auditory phenotypes of MYO15A variants according to the affected domain and the feasibilities for acoustic stimulation. We conducted whole-exome sequencing for 10 unrelated individuals from seven multiplex families with DFNB3; 11 MYO15A variants, including the novel frameshift c.900delT (p.Pro301Argfs*143) and nonsense c.4879G > T (p.Glu1627*) variants, were identified. In seven probands, residual hearing at low frequencies was significantly higher in the groups with one or two N-terminal frameshift variants in trans conformation compared to that in the group without these variants. This is consistent with the 56 individuals from the previously published reports that carried a varying number of N-terminal truncating variants in MYO15A. In addition, patients with missense variants in the second FERM domain had better hearing at low frequencies than patients without these variants. Subsequently, acoustic stimulation provided by devices such as hearing aids or cochlear implants was feasible in patients with one or two N-terminal truncating variants or a second FERM missense variant. In conclusion, N-terminal or second FERM variants in MYO15A allow the practical use of acoustic stimulation through hearing aids or electroacoustic stimulation for aural rehabilitation. [ABSTRACT FROM AUTHOR]