Search Results (89)

Background/Objectives: Pathogenic recessive GJB2 variants are the main genetic cause of non-syndromic sensorineural hearing loss. However, following GJB2 testing, a significant proportion of deaf patients are only found to be heterozygous carriers of pathogenic GJB2 alleles. Five large deletions not affecting GJB2 but encompassing a minimal common 62 kb region within the neighbouring CRYL1 gene have been described to cause loss of cis GJB2 expression and, as a result, produce hearing loss when in trans with pathogenic GJB2 variants. We describe the identification and characterization of a novel deletion of this type in deaf patients from northwestern Spain. Methods: We used panel NGS sequencing to detect the deletion, MLPA to validate it, whole-genome sequencing to map its breakpoints, PCR + Sanger sequencing to finely characterize it and triple-primer PCR to screen for it. Results: We identified a novel 200 kb deletion spanning the whole CRYL1 gene in two unrelated deaf patients from Asturias (in northwestern Spain) who were heterozygous for the pathogenic GJB2 c.35delG variant. Although the large deletion was absent from gnomAD v4.1.0 and 2052 local control alleles, screening for it in 20 additional deaf carriers of monoallelic pathogenic GJB2 variants detected it in another patient from Galicia (also in northwestern Spain). The novel deletion, termed del(200 kb)insATTATA, explained hearing loss in 3/43 (7%) deaf patients from our cohort that were otherwise heterozygous for pathogenic GJB2 variants. Conclusions: This work highlights the importance of comprehensively testing all genomic regions known to be clinically relevant for a given genetic condition, including thorough CRYL1 CNV screening for DFNB1A diagnostics. Full article

Recessive variants of SLC26A4 are a common cause of hereditary hearing impairment and are responsible for non-syndromic enlarged vestibular aqueducts and Pendred syndrome. Patients with bi-allelic SLC26A4 variants often suffer from fluctuating hearing loss and recurrent vertigo, ultimately leading to severe to profound hearing impairment. However, there are currently no satisfactory prevention or treatment options for this condition. The CRISPR/Cas9 genome-editing technique is a well-known tool for correcting point mutations or manipulating genes and shows potential therapeutic applications for hereditary disorders. In this study, we used the homology-independent targeted integration (HITI) strategy to correct the SLC26A4 c.919-2A>G variant, the most common SLC26A4 variant in the Han Chinese population. Next-generation sequencing was performed to evaluate the editing efficiency of the HITI strategy. The results showed that only 0.15% of the reads successfully exhibited HITI integration, indicating that the c.919-2 region may not be a suitable region for HITI selection. This suggests that other site selection or insertion strategies may be needed to improve the efficiency of correcting the SLC26A4 c.919-2A>G variant. This experience may serve as a valuable reference for other researchers considering CRISPR target design in this region. Full article

Background: Meniere’s disease (MD) is a set of rare disorders that affects >4 million people worldwide. Individuals with MD suffer from episodes of vertigo associated with fluctuating sensorineural hearing loss and tinnitus. Hearing loss can involve one or both ears. Over 10% of the reported cases are observed in families, suggesting its significant genetic contribution. The condition is polygenic with >20 genes, and several patterns of inheritance have been reported, including autosomal dominant, autosomal recessive, and digenic inheritance across multiple MD families. Preclinical research using animal models has been an indispensable tool for studying the neurophysiology of the auditory and vestibular systems and to get a better understanding of the functional role of genes that are involved in the hearing and vestibular dysfunction. While mouse models are the most used preclinical model, this review analyzes alternative animal and non-animal models that can be used to study MD genes. Methods: A literature search of the 21 genes reported for familial MD and the preclinical models used to investigate their functional role was performed. Results: Comparing the homology of proteins encoded by these genes to other model organisms revealed Drosophila and zebrafish as cost-effective models to screen multiple genes and study the pathophysiology of MD. Conclusions: Murine models are preferred for a quantitative neurophysiological assessment of hearing and vestibular functions to develop drug or gene therapy. Full article

Background: Alport syndrome (AS) is one of the most common monogenic kidney disorders. Recent studies have highlighted the modifier effect of variants involving podocyte and non-collagenous extracellular matrix (ECM) proteins in AS. Methods: We report a case series of eight patients with genetically proven AS and simultaneous variants involving podocyte and non-collagenous ECM proteins. Our aim is to describe the influence of such variants on the phenotype of patients with AS. Results: We identified 10 different type IV collagen variants. Patients were diagnosed with autosomal dominant (3/8), autosomal recessive (2/8), digenic (2/8) and X-linked AS (1/8). There were eight different variants involving podocyte and non-collagenous ECM proteins. The genes involved were CRB2, LAMA5, LAMB2, NUP107, MYO1E and PLCE1. Four patients (LAMB2, LAMA5 and PLCE1 variants) presented with nephrotic syndrome or nephrotic range proteinuria. Two patients had hearing loss. Most patients (7/8) had a family history of kidney disease. Two patients (LAMB2 and LAMA5 variants) were diagnosed with focal segmental glomerulosclerosis. Two patients developed end-stage kidney disease (LAMA5, MYO1E and NUP107 variants). Conclusions: Although mutations of podocyte and ECM proteins do not have phenotypic expression in monoallelic form, the presence of such variants could explain the phenotypic variability of AS. Full article

Background/Objectives: Hearing loss is one of the most common sensorineural impairments, and approximately 60% of early-onset cases are due to genetic variations. The otogelin-like protein, encoded by the OTOGL gene, is a component of the acellular membranes of the inner ear, such as the tectorial membrane, and is thought to play an important role in cochlear amplification. OTOGL gene variants are a rare cause of hearing loss such as DFNB84B, a mild-to-moderate sensorineural hearing loss presenting in early childhood with autosomal recessive inheritance. In this study, we aim to enhance our comprehension of the phenotypes of hearing loss caused by OTOGL variants. Methods: A total of 7056 Japanese patients with hearing loss were recruited, and based on massively parallel DNA sequencing on 158 target genes, we selected patients with biallelic OTOGL variants. Results: Ten affected individuals with OTOGL gene variants were detected, the largest group of patients yet to be reported, and eight of the eleven variants were novel. Our results showed that variations in this gene led to mild-to-moderate non-progressive hearing loss, and the accompanying symptoms, mainly vestibular symptoms, were speculated to present in adulthood. Conclusions: Determination of the phenotypes of genes causative of hearing loss is expected to greatly benefit patients with hearing loss as it can assist in predicting outcomes and lead to appropriate intervention, which, in OTOGL-associated hearing loss cases, is based around the fact that the patients need not be concerned with deterioration in hearing, but require careful follow-up for vestibular symptoms. Full article

Background/Objectives: The OTOF gene is reported to be the causative gene for non-syndromic recessive sensorineural hearing loss and auditory neuropathy spectrum disorder. About 300 variants have been reported, but there have been no reports to date on copy gain variants. Methods: We identified a copy gain variant in the OTOF gene through short-read next-generation sequencing analysis from one patient with auditory neuropathy. We also performed long-read next-generation sequencing analysis using the Oxford Nanopore Technologies adaptive sampling procedure. Results: The four-year-old male carried a duplication of chr2: 26,477,852 to 26,483,106 (a 5254-base duplication including exon 14 to exon 18 of the OTOF gene NM_001287489) and a c.5385C>A single nucleotide variant. We also confirmed that these two variants were located in the trans configuration based on haplotype phasing results using the long-read next-generation sequencing data. Conclusions: This is the first report of an auditory neuropathy patient with a large duplication variant in the OTOF gene. The identified variants were novel, but based on the clinical phenotype of the patient, these variants seem to be the genetic cause of this patient’s phenotype. Oxford Nanopore Technologies adaptive sampling is a powerful tool for the analysis of structural variants (particularly for determining the breakpoint and direction) and haplotype phasing. Full article

Background/Objectives: MYO3A belongs to the unconventional myosin superfamily, and the myosin IIIa protein localizes on the tip of the stereocilia of vestibular and cochlear hair cells. Deficiencies in MYO3A have been reported to cause the deformation of hair cells into abnormally long stereocilia with an increase in spacing. MYO3A is a rare causative gene of autosomal recessive sensorineural hearing loss (DFNB30), with only 13 cases reported to date. In this study, we aimed to elucidate the phenotypes caused by MYO3A variations. Methods: Massively parallel DNA sequencing was performed on 15,684 Japanese hearing loss patients (mean age 27.5 ± 23.1 years old, 6574 male, 8612 female and 498 patients for whom information was unavailable), identifying nine candidate patients with MYO3A variants. Results: We identified eight causative MYO3A variants by massively parallel DNA sequencing, including six novel variants, and reported nine individuals possessing MYO3A gene variants, which is the largest group of non-related patients yet to be detected. Our findings confirmed that MYO3A variants cause progressive hearing loss, with its onset varying from birth to the second decade, eventually leading to severe-to-profound hearing loss. Conclusions: We clarified that patients with MYO3A gene variants present with late-onset, progressive hearing loss. Our findings have enabled us to predict the outcomes of hearing loss in patients with candidate MYO3A gene variants and to provide intervention in a timely manner. Full article

Background/Objectives: The OTOG gene is responsible for autosomal recessive non-syndromic sensorineural hearing loss and is assigned as DFNB18B. To date, 44 causative OTOG variants have been reported to cause non-syndromic hearing loss. However, the detailed clinical features for OTOG-associated hearing loss remain unclear. Methods: In this study, we analyzed 7065 patients with non-syndromic hearing loss (mean age 26.4 ± 22.9 years, 2988 male, 3855 female, and 222 without gender information) using massively parallel DNA sequencing for 158 target deafness genes. We identified the patients with biallelic OTOG variants and summarized the clinical characteristics. Results: Among the 7065 patients, we identified 14 possibly disease-causing OTOG variants in 26 probands, with 13 of the 14 variants regarded as novel. Patients with OTOG-associated hearing loss mostly showed congenital or childhood-onset hearing loss. They were considered to show non-progressive, mild-to-moderate hearing loss. There were no symptoms that accompanied the hearing loss in OTOG-associated hearing loss patients. Conclusions: We confirmed non-progressive, mild-to-moderate hearing loss as the clinical characteristics of OTOG-associated hearing loss. These findings will contribute to a better understanding of the clinical features of OTOG-associated HL and will be useful in clinical practice. Full article

Background: WFS1-spectrum disorders are caused by a mutation in the WFS1 gene. The term includes a wide range of rare disorders, from the most severe Wolfram syndrome with autosomal recessive inheritance to milder clinical manifestations with a single causative variant in the WFS1 gene, such as Wolfram-like syndrome, low-frequency sensorineural hearing loss (LFSNHL), isolated diabetes mellitus (DM), nonsyndromic optic atrophy (OA), and isolated congenital cataracts. Methods: The aim of this study was to evaluate genotype–phenotype correlations in Polish patients with WFS1-spectrum disorders. The study group constituted 22 patients (10 F; 12 M), including 10 patients (3 F; 7 M) referred to the Outpatient Clinic for Rare Diseases in Children and Adolescents and Diabetogenetics between 2019 and 2024 with clinical symptoms suggestive of WFS1-spectrum disorders, and 12 of their first-degree relatives (7 F; 5 M) from 10 families in Poland. Molecular testing was performed using tNGS (Targeted Next Generation Sequencing; Illumina) and analyzed for variants in the WFS1 gene. Results: Thirteen different variants in the WFS1 gene were found in 22 individuals (10 patients and family members), including the identification of two new variants (c.1535T>C and c.2485C>G). All patients had hyperglycemia or DM, hearing impairment, OA, or a combination of these symptoms. Four patients in the study group were diagnosed with Wolfram syndrome and all were compound heterozygotes for variants in the WFS1 gene. Conclusions: The evaluation of molecular characteristics in combination with clinical symptoms broadens the understanding of WFS1-spectrum disorders and allows more accurate management and prognosis for patients with this diagnosis. Full article

Pathogenic variants in the USH2A gene are the primary cause of both non-syndromic autosomal recessive inherited retinitis pigmentosa (RP) and the syndromic form, characterized by retinal degeneration and sensorineural hearing loss. This study presents a comparative assessment of the genetic variant spectrum in the USH2A gene among Russian patients in two clinical groups. A retrospective analysis was conducted on massive parallel panel sequencing data from 2415 blood samples of unrelated patients suspected of having hereditary retinal diseases. The copy number of USH2A exons was determined using the quantitative MLPA method with the MRC-Holland SALSA MLPA kit. Biallelic pathogenic and likely pathogenic variants in the USH2A gene were identified in 69 patients (8.7%). In the group of patients with isolated hereditary RP (55 patients), the most frequent pathogenic variants were p.(Glu4445_Ser4449delinsAspLeu) (20.9%), p.(Trp3955*) (15.5%), and p.(Cys934Trp) (5.5%). In patients with the syndromic form (14 patients), the most frequent variants were p.(Trp3955*) (35.7%) and c.8682-9A>G (17.9%). It was found that patients with isolated vision impairment rarely had two “null” variants (17.8%), whereas this was common among patients with both hearing and vision impairment (71.4%) (p ≤ 0.05), explaining the severity of the disease and the earlier onset of clinical symptoms in the syndromic form of RP. Ten previously undescribed loss-of-function variants were identified. The estimated prevalence of USH2A-associated retinal dystrophy in Russia was 1.9 per 100,000 individuals. The obtained data on the differences in the spectra of genetic variants in the USH2A gene in the two studied groups highlight the importance of establishing genotype–phenotype correlations and predicting disease severity, aiming at potential early cochlear implantation and selection of target therapy. Full article

Background/Objectives: Hearing loss (HL) is a significant global health concern, affecting approximately 1 in every 1000 newborns, with over half of these cases attributed to genetic factors. This study focuses on identifying the genetic basis of autosomal recessive non-syndromic hearing loss (ARNSHL) in a consanguineous Emirati family. Methods: Clinical exome sequencing (CES) was performed on affected members of the family, followed by Sanger sequencing to validate the findings. Specific primers were used for PCR amplification of target CDH23 exons. Mutations were analyzed using various computational tools to assess their pathogenicity. Results: We identified two heterozygous mutations in the CDH23 gene: a novel nonsense variant (c.264G>A, p.Trp88Ter) and a missense variant (c.5168G>A, p.Arg1723His). Both mutations were found in trans configuration, suggesting a compound heterozygous state contributing to the phenotype. In silico analysis predicted a significant impact on protein function, potentially leading to the observed ARNSHL. Conclusions: This study emphasizes the complexity of genetic factors in hearing loss, particularly in highly consanguineous populations. The identification of both nonsense and missense mutations in the CDH23 gene enhances understanding of its role in hearing loss and provides essential insights for genetic counseling and future therapeutic strategies. Full article

Background: Alport syndrome (AS) is a genetic disorder characterized by progressive renal disease, ocular abnormalities, and sensorineural hearing loss. However, the audiological profile of patients with AS remains elusive. Thus, this study aims to evaluate the natural history of auditory function in patients with AS. Methods: Exome or targeted sequencing for deafness genes was performed to confirm the pathogenic variants in patients with AS. Results: We identified fifteen individuals with AS who carried pathogenic variants of COL4A3, COL4A4, or COL4A5. Among fifteen, twelve (80%) showed hematuria, and six (40%) showed proteinuria. The patients exhibited bilateral sensorineural hearing loss, which was progressive and symmetric. The hearing thresholds increased according to age and plateaued at the level of 53 dB HL, indicating the hearing loss did not reach the severe-to-moderate level. The auditory dysfunction showed a distinct natural history depending on the inheritance pattern, but there was no remarkable difference between males and females among X-linked AS. Conclusions: Auditory dysfunction in AS is progressive up to the level of moderate hearing loss. Precise auditory rehabilitation for patients with AS is warranted depending on the inheritance pattern and genetic predisposition. Full article

Dysfunction of some mitochondrial aminoacyl-tRNA synthetases (encoded by the KARS1, HARS2, LARS2 and NARS2 genes) results in a great variety of phenotypes ranging from non-syndromic hearing impairment (NSHI) to very complex syndromes, with a predominance of neurological signs. The diversity of roles that are played by these moonlighting enzymes and the fact that most pathogenic variants are missense and affect different domains of these proteins in diverse compound heterozygous combinations make it difficult to establish genotype–phenotype correlations. We used a targeted gene-sequencing panel to investigate the presence of pathogenic variants in those four genes in cohorts of 175 Spanish and 18 Colombian familial cases with non-DFNB1 autosomal recessive NSHI. Disease-associated variants were found in five cases. Five mutations were novel as follows: c.766C>T in KARS1, c.475C>T, c.728A>C and c.1012G>A in HARS2, and c.795A>G in LARS2. We provide audiograms from patients at different ages to document the evolution of the hearing loss, which is mostly prelingual and progresses from moderate/severe to profound, the middle frequencies being more severely affected. No additional clinical sign was observed in any affected subject. Our results confirm the involvement of KARS1 in DFNB89 NSHI, for which until now there was limited evidence. Full article

Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six genes was identified. In one of the two sibships of this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) in the kinase domain of MAP3K1 co-segregated with nonsyndromic deafness. There are two previously reported Map3k1-kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. MAP3K1 phosphorylates serine and threonine and functions in a signaling pathway where pathogenic variants of HGF, MET, and GAB1 were previously reported to be associated with human deafness DFNB39, DFNB97, and DFNB26, respectively. Our single-cell transcriptome data of mouse cochlea mRNA show expression of Map3k1 and its signaling partners in several inner ear cell types suggesting a requirement of wild-type MAP3K1 for normal hearing. In contrast to dominant variants of MAP3K1 associated with Disorders of Sex Development 46,XY sex-reversal, our computational modeling of the recessive substitution p.(Arg1487His) predicts a subtle structural alteration in MAP3K1, consistent with the limited phenotype of nonsyndromic deafness. Full article

Hearing impairment, a rare inherited condition, is notably prevalent in populations with high rates of consanguinity. The most common form observed globally is autosomal recessive non-syndromic hearing loss. Despite its prevalence, this genetic disorder is characterized by a substantial genetic diversity, making diagnosis and screening challenging. The emergence of advanced next-generation sequencing (NGS) technologies has significantly advanced the discovery of genes and variants linked to various conditions, such as hearing loss. In this study, our objective was to identify the specific variant causing hearing loss in a family from Syria using clinical exome sequencing. The proband in the family exhibited profound deafness as shown by pure-tone audiometry results. The analysis of the different variants obtained by NGS revealed the presence of a nonsense mutation within the CLDN14 gene. Through Sanger sequencing, we verified that this variant segregates with the disease and was not present in the control population. Moreover, we conducted a comprehensive review of all reported deafness-related CLDN14 mutations and their associated phenotypes. Furthermore, we endeavored to carry out a comparative analysis between the CLDN14 and GJB2 genes, with the objective of identifying potential factors that could explain the notable discrepancy in mutation frequency between these two genes. Full article