scholarly journals Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss

2020 ◽  
Vol 8 (8) ◽  
Author(s):  
Jing Guan ◽  
Hongyang Wang ◽  
Lan Lan ◽  
Yusen Wu ◽  
Guohui Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
De Novo ◽  
Sensorineural Hearing ◽  
Pathogenic Variants

scholarly journals SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2380-2387 ◽  
Author(s):  
Alisdair McNeill ◽  
Emanuela Iovino ◽  
Luke Mansard ◽  
Christel Vache ◽  
David Baux ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Developmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Sensorineural Deafness ◽  
Sensorineural Hearing ◽  
De Novo Mutation ◽  
Xenopus Laevis Oocytes ◽  
De Novo Mutations

Abstract The SLC12 gene family consists of SLC12A1–SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16–18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16–18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.

De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss

2001 ◽  
Vol 108 (3) ◽  
pp. 269-270 ◽  
Author(s):  
Andreas R Janecke ◽  
Doris Nekahm ◽  
Judith Löffler ◽  
Almut Hirst-Stadlmann ◽  
Thomas Müller ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
De Novo ◽  
Sensorineural Hearing ◽  
De Novo Mutation ◽  
Connexin 26

scholarly journals Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss

Hereditas ◽  
2020 ◽  
Vol 157 (1) ◽  
Author(s):  
Jing Yu ◽  
Wei Jiang ◽  
Li Cao ◽  
Xiaoxue Na ◽  
Jiyun Yang
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Motor Development ◽  
Sensorineural Hearing ◽  
Chinese Family ◽  
Targeted Next Generation Sequencing ◽  
Gross Motor Development ◽  
Pathogenic Variants ◽  
Perrault Syndrome ◽  
Ear Malformations

AbstractMutations in HARS2 are one of the genetic causes of Perrault syndrome, characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction. Here, we identified two novel putative pathogenic variants of HARS2 in a Chinese family with sensorineural hearing loss including two affected male siblings, c.349G > A (p.Asp117Asn) and c.908 T > C (p.Leu303Pro), through targeted next-generation sequencing methods. The two affected siblings (13 and 11 years old) presented with early-onset, rapidly progressive SNHL. The affected siblings did not have any inner ear malformations or delays in gross motor development. Combined with preexisting clinical reports, Perrault syndrome may be latent in some families with non-syndromic deafness associated with HARS2 mutations. The definitive diagnosis of Perrault syndrome based on clinical features alone is a challenge in sporadic males, and preadolescent females with no signs of POI. Our findings further expanded the existing spectrum of HARS2 variants and Perrault syndrome phenotypes, which will assist in molecular diagnosis and genetic counselling of patients with HARS2 mutations.

scholarly journals Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1031 ◽  
Author(s):  
Muhammad Noman ◽  
Rafaqat Ishaq ◽  
Shazia A. Bukhari ◽  
Zubair M. Ahmed ◽  
Saima Riazuddin
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Sensorineural Hearing ◽  
Low Frequencies ◽  
Locus Heterogeneity ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
Pakistani Families

Hearing loss is a genetically heterogeneous disorder affecting approximately 360 million people worldwide and is among the most common sensorineural disorders. Here, we report a genetic analysis of seven large consanguineous families segregating prelingual sensorineural hearing loss. Whole-exome sequencing (WES) revealed seven different pathogenic variants segregating with hearing loss in these families, three novel variants (c.1204G>A, c.322G>T, and c.5587C>T) in TMPRSS3, ESRRB, and OTOF, and four previously reported variants (c.208C>T, c.6371G>A, c.226G>A, and c.494C>T) in LRTOMT, MYO15A, KCNE1, and LHFPL5, respectively. All identified variants had very low frequencies in the control databases and were predicted to have pathogenic effects on the encoded proteins. In addition to being familial, we also found intersibship locus heterogeneity in the evaluated families. The known pathogenic c.226C>T variant identified in KCNE1 only segregates with the hearing loss phenotype in a subset of affected members of the family GCNF21. This study further highlights the challenges of identifying disease-causing variants for highly heterogeneous disorders and reports the identification of three novel and four previously reported variants in seven known deafness genes.

Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms

2020 ◽  
pp. jmedgenet-2020-106892
Author(s):  
Xue Gao ◽  
Sha-Sha Huang ◽  
Shi-Wei Qiu ◽  
Yu Su ◽  
Wei-Qian Wang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Noonan Syndrome ◽  
Sensorineural Hearing ◽  
Supporting Cells ◽  
Pathogenic Variants ◽  
Underlying Mechanisms ◽  
Ganglion Neurons ◽  
Multiple Lentigines

BackgroundGermline variants in PTPN11 are the primary cause of Noonan syndrome with multiple lentigines (NSML) and Noonan syndrome (NS), which share common skin and facial symptoms, cardiac anomalies and retardation of growth. Hearing loss is considered an infrequent feature in patients with NSML/NS. However, in our cohort, we identified a group of patients with PTPN11 pathogenic variants that were primarily manifested in congenital sensorineural hearing loss (SNHL). This study evaluated the incidence of PTPN11-related NSML or NS in patients with congenital SNHL and explored the expression of PTPN11 and the underlying mechanisms in the auditory system.MethodsA total of 1502 patients with congenital SNHL were enrolled. Detailed phenotype-genotype correlations were analysed in patients with PTPN11 variants. Immunolabelling of Ptpn11 was performed in P35 mice. Zebrafish with Ptpn11 knockdown/mutant overexpression were constructed to further explore mechanism underlying the phenotypes.ResultsTen NSML/NS probands were diagnosed via the identification of pathogenic variants of PTPN11, which accounted for ~0.67% of the congenital SNHL cases. In mice cochlea, Shp2, which is encoded by Ptpn11, is distributed in the spiral ganglion neurons, hair cells and supporting cells of the inner ear. In zebrafish, knockdown of ptpn11a and overexpression of mutant PTPN11 were associated with a significant decrease in hair cells and supporting cells. We concluded that congenital SNHL could be a major symptom in PTPN11-associated NSML or NS. Other features may be mild, especially in children.ConclusionScreening for PTPN11 in patients with congenital hearing loss and variant-based diagnoses are recommended.

scholarly journals Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zuzana Pavlenkova ◽  
Lukas Varga ◽  
Silvia Borecka ◽  
Miloslav Karhanek ◽  
Miloslava Huckova ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Sensorineural Hearing ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Causal Genes ◽  
Uncertain Significance

AbstractThe genetic heterogeneity of sensorineural hearing loss (SNHL) is a major hurdle to the detection of disease-causing variants. We aimed to identify underlying causal genes associated with mid-frequency hearing loss (HL), which contributes to less than about 1% of SNHL cases, by whole exome sequencing (WES). Thirty families segregating mid-frequency SNHL, in whom biallelic GJB2 mutations had been previously excluded, were selected from among 851 families in our DNA repository of SNHL. DNA samples from the probands were subjected to WES analysis and searched for candidate variants associated with SNHL. We were able to identify the genetic aetiology in six probands (20%). In total, we found three pathogenic and three likely pathogenic variants in four genes (COL4A5, OTOGL, TECTA, TMPRSS3). One more proband was a compound heterozygote for a pathogenic variant and a variant of uncertain significance (VUS) in MYO15A gene. To date, MYO15A and TMPRSS3 have not yet been described in association with mid-frequency SNHL. In eight additional probands, eight candidate VUS variants were detected in five genes (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR). Seven of these 16 variants have not yet been published or mentioned in the available databases. The most prevalent gene was TECTA, identified in 23% of all tested families. Furthermore, we confirmed the hypothesis that a substantive portion of cases with this conspicuous audiogram shape is a consequence of a genetic disorder.

scholarly journals Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G > A: Genotype–Phenotype Study and CI Management

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenjia Wang ◽  
Jin Li ◽  
Lan Lan ◽  
Linyi Xie ◽  
Fen Xiong ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Pure Tone ◽  
De Novo ◽  
Pure Tone Audiometry ◽  
Auditory Neuropathy ◽  
Neurological Symptoms ◽  
Sensorineural Hearing ◽  
Auditory Brainstem Responses ◽  
Capos Syndrome

Objective: The objective of this study is to analyze the genotype–phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and ATP1A3 c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome.Methods: Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing.Results: Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms.Conclusion:ATP1A3 p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific de novo mutation.

scholarly journals Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss

2021 ◽  
Author(s):  
Zuzana Pavlenkova ◽  
Lukas Varga ◽  
Silvia Borecka ◽  
Miloslav Karhanek ◽  
Miroslava Huckova ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Genetic Disorder ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Sensorineural Hearing ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Causal Genes ◽  
Uncertain Significance

Abstract The genetic heterogeneity of sensorineural hearing loss (SNHL) is a major hurdle to the detection of disease-causing variants. We aimed to identify underlying causal genes associated with mid-frequency hearing loss (HL), which contributes to less than about 1% of SNHL cases, by whole exome sequencing (WES). Thirty families segregating mid-frequency SNHL, in whom biallelic GJB2 mutations had been previously excluded, were selected from among 851 families in our DNA repository of SNHL. DNA samples from the probands were subjected to WES analysis and searched for candidate variants associated with SNHL. We were able to identify the genetic aetiology in six probands (20%). In total, we found three pathogenic and three likely pathogenic variants in four genes COL4A5, OTOGL, TECTA, TMPRSS3). One proband was a compound heterozygote for a pathogenic variant and a variant of uncertain significance (VUS) in MYO15A gene. To date, MYO15A and TMPRSS3 have not yet been described in association with mid-frequency SNHL. In eight additional probands, eight candidate VUS variants were detected in five genes (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR). Seven of these 16 variants have not yet been published or mentioned in the available databases. The most prevalent gene was TECTA, identified in 23% of all tested families. Furthermore, we confirmed the hypothesis that a substantive portion of cases with this conspicuous audiogram shape is a consequence of a genetic disorder.

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