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The current study investigated how the FOXI1 and KCNJ10 genes were affected in infants with a single-allele mutation in the SLC26A4 gene, and it determined the audiological phenotypes of infants with double heterozygous mutations (DHMs) in the three genes. Subjects were 562 infants with a single-allele SLC26A4 mutation detected during neonatal deafness genetic screening; the infants were seen as outpatients by Otology at Beijing Tongren Hospital. All subjects underwent SLC26A4 sequencing. Twenty infants had a second-allele variant while the remaining 542 had an SLC26A4 single-allele mutation. Infants also underwent FOXI1 and KCNJ10 sequencing. All patients with double heterozygous mutations in the aforementioned genes underwent an audiological evaluation and a limited imaging study; variants and audiological phenotypes were analyzed. Of 562 patients, 20 had SLC26A4 bi-allelic mutations; 8 carried single mutations in both SLC26A4 and KCNJ10. No pathogenic mutations in the FOXI1 gene were found. Four missense mutations in KCNJ10 were detected, including c.812G>A, c.800A>G, c.53G>A, and c.1042C>T. Eight individuals with a DHMs all passed universal newborn hearing screening, and all were found to have normal hearing. These data suggest that individuals with an SLC26A4 single-allele mutation, combined with FOXI1 or KCNJ10 gene mutations, do not suffer hearing loss during infancy, though this finding is worthy of further follow-up and in-depth discussion.

The current study retrospectively investigated variations in audiological phenotypes in children with GJB2 gene mutations. Subjects were 128 infants and young children who were seen as outpatients by Otology at Beijing Tongren Hospital from 2012 to 2018. Of the 128 subjects, 99 had biallelic truncating (T/T) mutations and 29 had truncating/nontruncating (T/NT) mutations. Genotypes, results of universal newborn hearing screening (UNHS), and the degree and symmetry of hearing loss were examined in the two groups. Twenty-two subjects (20.37%, 22/128) passed UNHS, including 13 children with T/T mutations and 9 with T/NT mutations. Of the 128 subjects, 22 had normal hearing, 2 had unilateral hearing loss, and 115 had bilateral hearing loss. Severe-to-profound hearing loss was the most prevalent phenotype in children with T/T mutations (73.23%), while normal hearing was prevalent in children with T/NT mutations (41.38%). Symmetrical hearing loss was the main phenotype in both groups, and the number of subjects with symmetrical hearing loss did not differ significantly between the two groups. Therefore, children with GJB2 gene mutations have phenotypic variability in terms of their results of UNHS and their degree and symmetry of hearing loss. Subjects with T/NT mutations of the GJB2 gene were more likely to pass UNHS and had milder hearing loss compared to those with T/T mutations. Symmetrical hearing loss was the main phenotype in the two groups, but 36.53% of children had bilateral asymmetric hearing loss. Parents of all subjects with sensorineural hearing loss were informed that their children may have a GJB2 mutation.

In order to investigate the genetic causes of hearing loss in a Chinese proband with nonsyndromic hearing loss and enlarged vestibular aqueduct (EVA), we conducted clinical and genetic evaluations in a deaf proband and her parents with normal hearing. 20 exons and flanking splice sites of the SLC26A4 gene were screened for pathogenic mutations by PCR amplification and bidirectional sequencing. As a control, a group of 400 healthy newborns from the same ethnic background were subjected to SLC26A4 gene screening using the same method. The proband harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. She was found to be heterozygous for a novel mutation c.574delC (p.Leu192Ter) in exon 5 and for the known mutation c.919-2A>G(c.IVS7-2A>G). Her mother was a heterozygous carrier of the c.919-2A>G mutation, and her father was a heterozygous carrier of the c.574delC and therefore co-segregated with the genetic disease. The c.574delC mutation was absent in 400 healthy newborns. The frameshift mutation causes the leucine (Leu) at amino acid position 192 to become a termination codon, leading to termination of protein sequence coding. This study demonstrates that the novel frameshift mutation c.574delC (p.Leu192Ter) in compound heterozygosity with c.919-2A>G in the SLC26A4 gene is the main cause of deafness in a family. Our study will expand the spectrum of known SLC26A4 mutations in the Chinese population, providing more information on genetic counseling, and diagnosis in hearing loss with EVA.

Abstract Objectives To identify second-allele variant in infants with a known single-allele mutation of the SLC26A4 gene and to determine the frequency of their occurrence; and to investigate the clinical audiological characteristics of infants with bi-allelic mutations in SLC26A4. Methods The study subjects were 371 patients with a single-allele SLC26A4 mutation detected by neonatal deafness gene screening (4 genes and 9 pathogenic variants) who were treated at the otology outpatient department of Beijing Tongren Hospital. The exonic and flanking splice site regions of the SLC26A4 gene were sequenced for all patients. All patients with bi-allelic SLC26A4 mutations underwent audiological evaluation, and some also underwent temporal bone computed tomography and/or inner ear magnetic resonance imaging. Results Of the 371 patients, 314 (84.64%) had an c.919-2A > G heterozygous mutation and 57 (15.36%) had a c.2168A > G (p.H723R) heterozygous mutation. 13 patients (3.50%) had a second-allele variant, including 11 (2.96%) with pathogenic mutations and 1 (0.27%) with a likely benign variant. Of the 13 patients with bi-allelic mutations, 11 had hearing loss and 2 had normal hearing, the latter of whom had c.919-2A > G/c.1766A > G and c.919-2A > G/c.757A > G compound heterozygous mutations, respectively. Four of the 13 patients with bi-allelic mutations had passed the universal newborn hearing screening, including 2 cases (15.38%) with hearing loss. The most prevalent degree of hearing loss was profound (40.91%), followed by severe (36.36%). The most prevalent audiometric configuration was sloping hearing loss (50.00%), followed by flat-type hearing loss (40.91%). Conclusions This is the first report in China of the frequency of occurrence of second-allele variant in infants with a known single-allele mutation of the SLC26A4 gene; the frequency was 3.50% for any type of variant and 2.96% for pathogenic mutations. A novel variant, c.1766A > G (p.Q589R), which is likely benign, was identified. The pathogenicity of c.757A > G (p.I253V) mutation deserves more in-depth research. For infants with bi-allelic SLC26A4 mutations, the degree of hearing loss was mainly severe-to-profound and the audiometric configuration was mainly sloping. [ABSTRACT FROM AUTHOR]