scholarly journals There is More Than Meets the Eye: Identification of Dual Molecular Diagnosis in Patients Affected by Hearing Loss

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 12
Author(s):  
Anna Morgan ◽  
Flavio Faletra ◽  
Giulia Severi ◽  
Martina La Bianca ◽  
Laura Licchetta ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Dual Diagnosis ◽  
Genetic Heterogeneity ◽  
Clinical Feature ◽  
Sensory Impairment ◽  
Clinical Genetic ◽  
Whole Exome ◽  
High Prevalence ◽  
Fitting In ◽  
First Time

Hearing loss (HL) is the most common sensory impairment, and it is characterized by a high clinical/genetic heterogeneity. Here we report the identification of dual molecular diagnoses (i.e., mutations at two loci that lead to the expression of two Mendelian conditions) in a series of families affected by non-syndromic and syndromic HL. Eighty-two patients who displayed HL as a major clinical feature have been recruited during the last year. After an accurate clinical evaluation, individuals have been analyzed through whole-exome sequencing (WES). This protocol led to the identification of seven families characterized by the presence of a dual diagnosis. In particular, based on the clinical and genetic findings, patients have been classified into two groups: a) patients with HL and distinct phenotypes not fitting in a known syndrome due to mutations at two loci (e.g., HL in association with Marfan syndrome) and b) patients with two genes involved in HL phenotype (e.g., TMPRSS3 and MYH14). These data highlight for the first time the high prevalence of dual molecular diagnoses in HL patients and suggest that they should be considered especially for those cases that depart from the expected clinical manifestation or those characterized by a significant intra-familiar variability.

scholarly journals Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Somayeh Khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh-Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

scholarly journals Whole-Exome Sequencing to Decipher the Genetic Heterogeneity of Hearing Loss in a Chinese Family with Deaf by Deaf Mating

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e109178 ◽  
Author(s):  
Jie Qing ◽  
Denise Yan ◽  
Yuan Zhou ◽  
Qiong Liu ◽  
Weijing Wu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Heterogeneity ◽  
Chinese Family ◽  
Whole Exome

scholarly journals Novel MYO15A Variants are Associated with Hearing Loss in the Two Iranian Pedigrees

2020 ◽  
Author(s):  
somayeh khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Clinical Evaluations ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.Methods: This study was a report on two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results: The implementation of WES to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) and its related variants was reported in the present study. Two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 were correspondingly identified and then segregations were confirmed using Sanger sequencing. According to online prediction tools, both identified variants seemed to have damaging effects.Conclusion: This study further supported the effectiveness of WES for genetic diagnosis of ARNSHL as a first approach.

scholarly journals Novel MYO15A Variants are Associated with Hearing Loss in the Two Iranian Pedigrees

2020 ◽  
Author(s):  
Somayeh Khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.Methods: This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families.Results: The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects.Conclusion: In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

scholarly journals A splice-site variant (c.3289-1G>T) in OTOF underlies profound hearing loss in a Pakistani kindred

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ashfaque Ahmed ◽  
Meng Wang ◽  
Rizwan Khan ◽  
Abid Ali Shah ◽  
Hui Guo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Splice Site ◽  
Full Range ◽  
Disease Phenotype ◽  
Profound Hearing Loss ◽  
Splicing Variant ◽  
Whole Exome ◽  
High Prevalence ◽  
Splicing Variants ◽  
Splice Site Variant

Abstract Background Hearing loss/deafness is a common otological disorder found in the Pakistani population due to the high prevalence of consanguineous unions, but the full range of genetic causes is still unknown. Methods A large consanguineous Pakistani kindred with hearing loss was studied. Whole-exome sequencing and Sanger sequencing were performed to search for the candidate gene underlying the disease phenotype. A minigene assay and reverse transcription polymerase chain reaction was used to assess the effect of splicing variants. Results The splicing variants of OTOF (NM_194248, c.3289-1G>T) cosegregated with the disease phenotype in this Pakistani family. The substitution of a single base pair causes the deletion of 10 bp (splicing variant 1) or 13 bp (splicing variant 2) from exon 27, which results in truncated proteins of 1141 and 1140 amino acids, respectively. Conclusion Our findings reveal an OTOF splice-site variant as pathogenic for profound hearing loss in this family.

scholarly journals The Promise of Whole-Exome Sequencing in Detecting Novel Variants of the MYO15A Gene in Two Iranian Pedigrees with Non-Syndromic Hearing Loss, A descriptive experimental study

2019 ◽  
Author(s):  
somayeh khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh Chaleshtori ◽  
Samira Asgharzadeh
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.Methods: This study was a report on two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families.Results: The implementation of WES to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) and its related variants was reported in the present study. Two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 were correspondingly identified and then segregations were confirmed using Sanger sequencing. According to online prediction tools, both identified variants seemed to have damaging effects.Conclusion: This study further supported the effectiveness of WES for genetic diagnosis of ARNSHL as a first approach.

scholarly journals A Splice-site Variant (C.3289-1G>T) in OTOF Underlies Profound Hearing Loss in a Pakistani Kindred

2020 ◽  
Author(s):  
ashfaque ahmed ◽  
Meng Wang ◽  
Rizwan Khan ◽  
Abid Ali Shah ◽  
Hui Guo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Splice Site ◽  
Full Range ◽  
Disease Phenotype ◽  
Profound Hearing Loss ◽  
Splicing Variant ◽  
Whole Exome ◽  
High Prevalence ◽  
Splicing Variants ◽  
Splice Site Variant

Abstract Background: Hearing loss/deafness is a common otological disorder found in the Pakistani population due to the high prevalence of consanguineous unions, but the full range of genetic causes is still unknown.Methods: A large consanguineous Pakistani kindred with hearing loss was studied. Whole-exome sequencing and Sanger sequencing were performed to search for the candidate gene underlying the disease phenotype. A minigene assay and reverse transcription polymerase chain reaction were used to assess the effect of splicing variants.Results: The splicing variants of OTOF (NM_194248, c.3289-1G>T) cosegregated with the disease phenotype in this Pakistani family. The substitution of a single base pair causes the deletion of 10 bp (splicing variant 1) or 13 bp (splicing variant 2) from exon 27, which results in truncated proteins of 1141 and 1140 amino acids, respectively.Conclusion: Our findings reveal an OTOF splice-site variant as pathogenic for profound hearing loss in this family.

scholarly journals Novel MYO15A Variants are Associated with Hearing Loss in the Two Iranian Pedigrees

2020 ◽  
Author(s):  
somayeh khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.Methods: This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results: The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects.Conclusion: In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL.

scholarly journals Factors Influencing Hearing Disability and Reduction in Disability among First-time Hearing Aid Users in Singapore

2020 ◽  
Vol 49 (12) ◽  
pp. 978-989
Author(s):  
Eu Chin Ho ◽  
KeXin Li ◽  
Warren Ming Wu Ong ◽  
Yen Tze Eileen Bei ◽  
Aruni Seneviratna
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hearing Aid ◽  
Pure Tone Audiometry ◽  
Sensorineural Hearing ◽  
Patient Counselling ◽  
Hearing Disability ◽  
Multivariable Models ◽  
Fitting In ◽  
First Time

Abstract Introduction: This study aims to examine the factors associated with self-reported hearing disability and early reduction in disability after first-time hearing aid (HA) fitting in Singapore. Methods: Retrospective record review of 1,068 subjects issued with HAs at a tertiary hospital from 2001 to 2013. Results: Subjects reporting ≥5 disabilities reduced from 90% to 24% after HA fitting. ‘Difficulty hearing in noise’ was the commonest disability before and after HA fitting, while ‘needs to increase volume of TV/radio’ was the disability with most improvement after fitting. In multivariable models, having worse pure tone audiometry (PTA) thresholds of the better hearing ear and being ethnically Chinese were associated with subjects reporting more hearing disabilities. A higher proportion of subjects reported a reduction rather than an absence of disability after HA fitting. In multivariable models, daily HA usage for ≥4 hours, sensorineural hearing loss (HL) and worse PTA thresholds of the better hearing ear were associated with reduction in more disabilities after HA fitting. Conclusion: Hearing disability is high among first-time HA users in Singapore. Ethnicity and PTA thresholds were associated with self-reported hearing disability. After HA fitting, higher daily HA usage, sensorineural HL, and worse PTA thresholds of the better hearing ear were associated with early reduction in disability. Patient counselling on the benefits of HL rehabilitation could focus on hearing disability rather than PTA thresholds. The management of patients’ expectations could focus on reducing rather than eliminating disability. Keywords: Epidemiology, hearing loss rehabilitation, quality of life, sensorineural hearing loss, uptake

scholarly journals High Genetic Heterogeneity in Chinese Patients With Waardenburg Syndrome Revealed by Next-Generation Sequencing

2021 ◽  
Vol 12 ◽  
Author(s):  
Sen Zhang ◽  
Hongen Xu ◽  
Yongan Tian ◽  
Danhua Liu ◽  
Xinyue Hou ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Sanger Sequencing ◽  
De Novo ◽  
Sensorineural Hearing ◽  
Chinese Patients ◽  
Waardenburg Syndrome ◽  
Genetic Causes ◽  
Whole Exome ◽  
First Time

ObjectiveThis study aimed to explore the genetic causes of probands who were diagnosed with Waardenburg syndrome (WS) or congenital sensorineural hearing loss.MethodsA detailed physical and audiological examinations were carried out to make an accurate diagnosis of 14 patients from seven unrelated families. We performed whole-exome sequencing in probands to detect the potential genetic causes and further validated them by Sanger sequencing in the probands and their family members.ResultsThe genetic causes for all 14 patients with WS or congenital sensorineural hearing loss were identified. A total of seven heterozygous variants including c.1459C > T, c.123del, and c.959-409_1173+3402del of PAX3 gene (NM_181459.4), c.198_262del and c.529_556del of SOX10 gene (NM_006941.4), and c.731G > A and c.970dup of MITF gene (NM_000248.3) were found for the first time. Of these mutations, we had confirmed two (c.1459C > T and c.970dup) are de novo by Sanger sequencing of variants in the probands and their parents.ConclusionWe revealed a total of seven novel mutations in PAX3, SOX10, and MITF, which underlie the pathogenesis of WS. The clinical and genetic characterization of these families with WS elucidated high heterogeneity in Chinese patients with WS. This study expands the database of PAX3, SOX10, and MITF mutations and improves our understanding of the causes of WS.

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