Auditory Neuropathy Spectrum Disorder (ANSD)—Clinical Characteristics and Pathogenic Variant Analysis of Three Nonsyndromic Deafness Families

Objective. To analyze the phenotypic features and pathogenic variants of three unrelated families presenting with nonsyndromic auditory neuropathy spectrum disorder (ANSD). Methods. Three recruited families that were affected by congenital deafness were clinically evaluated, including a detailed family history and audiological and radiological examination. The peripheral blood of all patients and their parents was collected for DNA extraction, and then, the exonic and flanking regions were enriched and sequenced using targeted capture and high-throughput sequencing technology. Bioinformatics analyses and the Sanger sequencing were carried out to screen and validate candidate pathogenic variants. The pathogenicity of candidate variants was evaluated by an approach that was based on the standards and guidelines for interpreting genetic variants as proposed by the American College of Medical Genetics and Genomics (ACMG). Results. Four patients in three families were diagnosed as nonsyndromic ANSD, and all exhibited OTOF gene mutations. Among them, two individuals in family 1 (i.e., fam 1-II-2 and fam 1-II-3) carried homozygous variants c.[2688del];[2688del] (NM_194248.3). Two individuals from family 2 (fam 2-II-1) and family 3 (fam 3-II-4) carried compound heterozygous variants c.[4960G>A];[1469C>G] and c.[2675A>G];[2977_2978del], respectively. Conclusions. Three unrelated pedigrees with ANSD were caused by pathogenic variants in the OTOF gene. Five mutations were found and included c.2688del, c.2675A>G, c.2977_2978del, c.4960G>A, and c.1469C>G, of which the first two are novel and expanded mutational spectrum of the OTOF gene, thus having important implications for genetic counseling of the family.

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Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

Bioscience Reports ◽

10.1042/bsr20193443 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 1

Author(s):

Chunli Wei ◽

Ting Xiao ◽

Jingliang Cheng ◽

Jiewen Fu ◽

Qi Zhou ◽

...

Keyword(s):

Novel Mutation ◽

Gene Mutations ◽

Chinese Family ◽

Compound Heterozygous ◽

Missense Mutations ◽

The Novel ◽

Pathogenic Variants ◽

Pathogenic Genes ◽

Compound Heterozygous Variants ◽

Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

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Auditory Neuropathy Spectrum Disorder due to Two Novel Compound Heterozygous OTOF Mutations in Two Chinese Families

Neural Plasticity ◽

10.1155/2019/9765276 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Yue Qiu ◽

Sen Chen ◽

Le Xie ◽

Kai Xu ◽

Yi Lin ◽

...

Keyword(s):

Novel Mutation ◽

Pathogenic Mutation ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Unique Type ◽

Chinese Families ◽

Auditory Neuropathy Spectrum Disorder ◽

Mutation Database ◽

Next Generation Sequencing Ngs

Auditory neuropathy spectrum disorder (ANSD), also called auditory neuropathy (AN), is a unique type of prelingual hearing impairment. Up to 10% of deaf infants and children are affected by this disease. Mutation of the OTOF gene which encodes otoferlin is the common cause of congenital nonsyndromic ANSD. To date, over 110 mutations have been identified in the OTOF gene according to the Human Gene Mutation Database (HGMD). Here, next-generation sequencing (NGS) revealed that the compound heterozygous mutations c.4748G>A/c.2523+1G>T and c.5248G>C/c.5098G>C of the OTOF gene were present in two Chinese ANSD patients. Each patient had a known pathogenic mutation (c.4748G>A or c.5098G>C) and a novel mutation (c.2523+1G>T or c.5248G>C). Comparative amino acid sequence analysis across different species revealed that the residues at these novel mutation sites are evolutionarily highly conservative. This indicated that the novel mutations were possible causes of the disorder in the patients. Our findings extend the OTOF mutation spectrum and further confirm the role of the OTOF gene in ANSD.

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Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder

BMC Medical Genetics ◽

10.1186/s12881-017-0400-0 ◽

2017 ◽

Vol 18 (1) ◽

Cited By ~ 3

Author(s):

Fengzhu Tang ◽

Dengke Ma ◽

Yulan Wang ◽

Yuecai Qiu ◽

Fei Liu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Auditory Neuropathy Spectrum Disorder ◽

Whole Exome ◽

Compound Heterozygous Mutations

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Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder

Genes ◽

10.3390/genes13010149 ◽

2022 ◽

Vol 13 (1) ◽

pp. 149

Author(s):

María Domínguez-Ruiz ◽

Montserrat Rodríguez-Ballesteros ◽

Marta Gandía ◽

Elena Gómez-Rosas ◽

Manuela Villamar ◽

...

Keyword(s):

Hearing Impairment ◽

Autosomal Recessive ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Gene Encoding ◽

Auditory Neuropathy Spectrum Disorder ◽

Familial Cases ◽

Pathogenic Variants ◽

Cochlear Hearing Loss ◽

Syndromic Hearing Impairment

Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.

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Identification of novel OTOF compound heterozygous mutations by targeted next-generation sequencing in a Chinese patient with auditory neuropathy spectrum disorder

International Journal of Pediatric Otorhinolaryngology ◽

10.1016/j.ijporl.2013.08.007 ◽

2013 ◽

Vol 77 (10) ◽

pp. 1749-1752 ◽

Cited By ~ 12

Author(s):

Lu-ping Zhang ◽

Yong-Chuan Chai ◽

Tao Yang ◽

Hao Wu

Keyword(s):

Next Generation Sequencing ◽

Chinese Patient ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Next Generation ◽

Auditory Neuropathy Spectrum Disorder ◽

Targeted Next Generation Sequencing ◽

Compound Heterozygous Mutations ◽

Generation Sequencing

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Auditory testing outcomes with hearing aids in patients with auditory neuropathy spectrum disorder

American Journal of Otolaryngology ◽

10.1016/j.amjoto.2021.103057 ◽

2021 ◽

Vol 42 (5) ◽

pp. 103057

Author(s):

Firas Sbeih ◽

Donald M. Goldberg ◽

Sara Liu ◽

Maxwell Y. Lee ◽

Gina Stillitano ◽

...

Keyword(s):

Hearing Aids ◽

Auditory Neuropathy ◽

Spectrum Disorder ◽

Auditory Neuropathy Spectrum Disorder

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Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽

10.3390/genes12071053 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1053

Author(s):

Jasleen Dhaliwal ◽

Ying Qiao ◽

Kristina Calli ◽

Sally Martell ◽

Simone Race ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Variable Effect ◽

Gabaergic Neurotransmission ◽

High Heritability ◽

Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

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