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Background: Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is a rare autosomal recessive neurological disorder caused by mutations in the SLC52A2 gene, which is characterized by early childhood onset of sensorineural hearing loss, bulbar palsy, peripheral neuropathy, and respiratory insufficiency. We aimed to investigate the genetic cause of a 4-year-old boy who suffered from BVVLS2 whose initial presentation was severe normocytic anemia and had been overlooked for three years in a local hospital. He was misdiagnosed with pure red cell aplasia (PRCA) and treated with hormones and chemotherapy drugs, but there was no obvious effect., Methods: The targeted capture of 927 genes associated with neuromuscular disorders and next-generation sequencing were performed. Sanger sequencing was employed to verify the variant mutations., Results: The proband was found to be heterozygous for c.350T > C (p.L117P) in exon 3 and c.1135_1137delTGG (p.W379del) in exon 5 of SLC52A2 gene. His anemia and neurological symptoms improved significantly after treatment with low dose oral riboflavin., Conclusions: This study expands the mutational spectrum of SLC52A2 and phenotypic spectrum of BVVLS2, which provides a foundation for further investigations elucidating the SLC52A2 related mechanisms of BVVLS2. A low-dosage of riboflavin supplementation was used to obtain good curative effect, which provides further future references for the clinical treatments of BVVLS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: To identity the genetic causes of hearing loss in a Han Chinese family with enlarged vestibular aqueduct syndrome., Methods: Multiplex PCR technology combined with Ion Torrent™ next-generation sequencing technology was used to search for pathogenic mutations. A group of 1500 ethnically-matched normal hearing subjects screened for mutations in deafness-related genes using the same method in previously studied were included as a control., Results: The proband and his little sister suffered from typical features of sensorineural hearing loss with enlarged vestibular aqueduct (EVA). Both subjects harbored two compound heterozygous mutations in the SLC26A4 gene. A novel mutation named c.2110 G > C (p.Glu704Gln) in exon 19 and another previously reported mutation c.1673 A > T (p.Asn558Ile) were identified. These mutations were carried in the heterozygous state by the parents and therefore co-segregated with the genetic disease. The c.2110 G > C (p.Glu704Gln) mutation was absent in 1500 healthy newborns. Protein alignment indicated high evolutionary conservation of the p.E704 residue, and this mutation was predicted by online tools to be damaging and deleterious., Conclusion: This study demonstrates that the novel mutation c.2110 G > C (p.Glu704Gln) in compound heterozygosity with c.1673 A > T (p.Asn558Ile) in the SLC26A4 gene corresponds to the EVA in this family. Our study will provide a foundation for elucidating the SLC26A4-related mechanisms of hearing loss., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To explore the pathogenic causes of a proband who was diagnosed with non-syndromic hearing loss., Methods: We performed targeted capture of 159 known deafness-related genes and next-generation sequencing in the proband who was tested negative for the twenty hotspot variants in four common deafness-related genes(GJB2, GJB3, SLC26A4 and MTRNR1); Clinical reassessments, including detailed audiological and ocular examinations were performed in the proband and his normal parents., Results: We identified a novel heterozygous variant of CDH23:c.4567A > G (p.Asn1523Asp) in exon 37 (NM_022124), in conjunction with a reported mutation of CDH23:c.5101G > A (p.Glu1701Lys) in exon 40, to be a potentially pathogenic compound heterozygosity in the proband. The unaffected father has a heterozygous variant of CDH23:c.4567A > G, and the normal mother has another heterozygous variant, CDH23:c.5101G > A. The novel variant was absent in the 1000 Genomes Project. The clinical reassessments revealed binaural profound sensorineural hearing loss (DFNB12) without retinitis pigmentosa in the proband., Conclusions: This study demonstrates that the novel variant c.4567A > G (p.Asn1523Asp) in compound heterozygosity with c.5101G > A (p. Glu1701Lys) in the CDH23 gene is the main cause of DFNB12 in the proband. Simultaneously, this study provides a foundation to further elucidate the CDH23-related mechanisms of DFNB12., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: We aimed to investigate the genetic causes of hearing loss in a Chinese proband with nonsyndromic hearing loss and enlarged vestibular aqueduct syndrome., Methods: We conducted clinical and genetic evaluations in a deaf proband and his normal-hearing parents. Multiplex PCR technology combined with Ion Torrent™ next-generation sequencing technology was used to detect the pathogenic mutations. As a control, a group of 1500 previously studied healthy newborns from the same ethnic background were subjected to deafness gene screening using the same method as in our previous study., Results: The proband harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. He was found to be heterozygous for a novel mutation named c.1742 G > T (p.Arg581Met) in exon 13 and for the known mutation c.589 G > A (p.Gly197Arg). These variants were carried in the heterozygous state by the parents and therefore co-segregated with the genetic disease. The c.1742 G > T (p.Arg581Met) mutation was absent in 1500 healthy newborns. Protein alignment indicated high evolutionary conservation of the p.R581 residue, and this mutation was predicted by PolyPhen-2 and other online tools to be damaging., Conclusion: This study demonstrates that the novel mutation c.1742 G > T (p.Arg581Met) in compound heterozygosity with c.589 G > A in the SLC26A4 gene is the main cause of deafness in a family clinically diagnosed with enlarged vestibular aqueduct (EVA). Our study will provide a basic foundation for further investigations to elucidate the SLC26A4-related mechanisms of hearing loss., (Copyright © 2017 Elsevier B.V. All rights reserved.)