Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans

Lee, Sang Yeon; Han, Jin Hee; Kim, Bong Jik; Oh, Seung Ha; Lee, Seungmin; Oh, Doo Yi; Choi, Byung Yoon

doi:10.3390/ijms20174174

Cited by 17 publications

(13 citation statements)

References 28 publications

(57 reference statements)

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“…In a study of the clinical phenotype of USH1B, patients developed severe bilateral hearing loss at an average age of 5 months. On average, patients were walking consistently by 18 months of age (95% CI ±1 month), with all patients reporting vestibular symptoms (Lenassi et al 2014; Testa et al 2017). They began to experience night blindness at an average age of 13 years (95% CI ±1 year) with decreases in visual acuity reported at an average age of 16 (95% CI ±3 years).…”

Section: Usher Syndrome Type Imentioning

confidence: 99%

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Review of Genotype-Phenotype Correlations in Usher Syndrome

et al. 2021

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Usher syndrome (USH) encompasses a group of clinically and genetically heterogenous disorders defined by the triad of sensorineural hearing loss (SNHL), vestibular dysfunction, and vision loss. USH is the most common cause of deaf blindness. USH is divided clinically into three subtypes—USH1, USH2, and USH3—based on symptom severity, progression, and age of onset. The underlying genetics of these USH forms are, however, significantly more complex, with over a dozen genes linked to the three primary clinical subtypes and other atypical USH phenotypes. Several of these genes are associated with other deaf-blindness syndromes that share significant clinical overlap with USH, pointing to the limits of a clinically based classification system. The genotype-phenotype relationships among USH forms also may vary significantly based on the location and type of mutation in the gene of interest. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to USH. Currently, the state of knowledge varies widely depending on the gene of interest. Recent studies utilizing next-generation sequencing technology have expanded the list of known pathogenic mutations in USH genes, identified new genes associated with USH-like phenotypes, and proposed algorithms to predict the phenotypic effects of specific categories of allelic variants. Further work is required to validate USH gene causality, and better define USH genotype-phenotype relationships and disease natural histories—particularly for rare mutations—to lay the groundwork for the future of USH treatment.

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Section: Usher Syndrome Type Imentioning

confidence: 99%

“…They began to experience night blindness at an average age of 13 years (95% CI ±1 year) with decreases in visual acuity reported at an average age of 16 (95% CI ±3 years). Fifty percent of patients reached legal blindness by age 40 (Lenassi et al 2014; Testa et al 2017).…”

Section: Usher Syndrome Type Imentioning

confidence: 99%

Review of Genotype-Phenotype Correlations in Usher Syndrome

et al. 2021

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“…Regarding non-syndromic deafness genes, compound heterozygous variants of MYO15A were identified in four sporadic cases (families 1470, 1540, 1479, and 1688); compound heterozygous variants of CDH23 in two sporadic cases (families 1644 and 1528); and compound heterozygous variants of PDZD7 in families 1397 and 1597; all three candidate PDZD7 variants mapped to exon 4 in regions encoding one of the PDZ domains, which are structural anchors that tether the protein to cytoskeletal components [ 31 ]. Although ADGRV1 and PDZD7 have been proposed as genes responsible for Usher syndrome type IIC [ 32 ], no candidate variants of ADGRV1 were detected among our patients.…”

Section: Resultsmentioning

confidence: 99%

Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes

Mutai

Momozawa

Kamatani

et al. 2022

Orphanet J Rare Dis

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Background Heterogeneous genetic loci contribute to hereditary hearing loss; more than 100 deafness genes have been identified, and the number is increasing. To detect pathogenic variants in multiple deafness genes, in addition to novel candidate genes associated with hearing loss, whole exome sequencing (WES), followed by analysis prioritizing genes categorized in four tiers, were applied. Results Trios from families with non-syndromic or syndromic hearing loss (n = 72) were subjected to WES. After segregation analysis and interpretation according to American College of Medical Genetics and Genomics guidelines, candidate pathogenic variants in 11 previously reported deafness genes (STRC, MYO15A, CDH23, PDZD7, PTPN11, SOX10, EYA1, MYO6, OTOF, OTOG, and ZNF335) were identified in 21 families. Discrepancy between pedigree inheritance and genetic inheritance was present in one family. In addition, eight genes (SLC12A2, BAIAP2L2, HKDC1, SVEP1, CACNG1, GTPBP4, PCNX2, and TBC1D8) were screened as single candidate genes in 10 families. Conclusions Our findings demonstrate that four-tier assessment of WES data is efficient and can detect novel candidate genes associated with hearing loss, in addition to pathogenic variants of known deafness genes.

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“…The OTOF variants (Glu841Lys, Arg1856Trp, Leu1011Pro, Tyr1064Ter, and Arg1939Gln) were highly prevalent among Korean subjects with prelingual ANSD [ 6 , 20 , 24 ]. Subsequently, exome sequencing was performed to verify that the subjects did not carry convincing variants in the deafness panel, followed by bioinformatics analyses, as described previously [ 25 , 26 ]. The resulting readings were compared to the UCSC hg19 reference genome, and non-synonymous SNPs were filtered with a depth = 40; dbSNP138 was filtered out, except for the flagged SNP.…”

Section: Methodsmentioning

confidence: 99%

“…The resulting readings were compared to the UCSC hg19 reference genome, and non-synonymous SNPs were filtered with a depth = 40; dbSNP138 was filtered out, except for the flagged SNP. Using a comprehensive filtering process, rare single-nucleotide variations, indels, or splice-site variants were chosen, as described in our previous studies [ 25 , 26 ]. Subsequently, Sanger sequencing and segregation analyses were used to confirm the variant of the candidate deafness genes.…”

Section: Methodsmentioning

confidence: 99%

Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study

et al. 2021

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The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited “absent” or “anomalous” P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research.

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Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans

Cited by 17 publications

References 28 publications

Review of Genotype-Phenotype Correlations in Usher Syndrome

Review of Genotype-Phenotype Correlations in Usher Syndrome

Whole exome analysis of patients in Japan with hearing loss reveals high heterogeneity among responsible and novel candidate genes

Central auditory maturation and behavioral outcomes after cochlear implantation in prelingual auditory neuropathy spectrum disorder related to OTOF variants (DFNB9): Lessons from pilot study

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