scholarly journals Different Rates of the SLC26A4-Related Hearing Loss in Two Indigenous Peoples of Southern Siberia (Russia)

Diagnostics ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 2378
Author(s):  
Valeriia Yu. Danilchenko ◽  
Marina V. Zytsar ◽  
Ekaterina A. Maslova ◽  
Marita S. Bady-Khoo ◽  
Nikolay A. Barashkov ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Genetic Diagnosis ◽  
Unknown Etiology ◽  
Pendred Syndrome ◽  
Genetic Causes ◽  
Asian Populations ◽  
Slc26a4 Gene ◽  
Medical Genetic Services ◽  
First Time ◽  
Local Healthcare

Hereditary hearing loss (HL) is known to be highly locus/allelic heterogeneous, and the prevalence of different HL forms significantly varies among populations worldwide. Investigation of region-specific landscapes of hereditary HL is important for local healthcare and medical genetic services. Mutations in the SLC26A4 gene leading to nonsyndromic recessive deafness (DFNB4) and Pendred syndrome are common genetic causes of hereditary HL, at least in some Asian populations. We present for the first time the results of a thorough analysis of the SLC26A4 gene by Sanger sequencing in the large cohorts of patients with HL of unknown etiology belonging to two neighboring indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians). A definite genetic diagnosis based on the presence of biallelic SLC26A4 mutations was established for 28.2% (62/220) of all enrolled Tuvinian patients vs. 4.3% (4/93) of Altaian patients. The rate of the SLC26A4-related HL in Tuvinian patients appeared to be one of the highest among populations worldwide. The SLC26A4 mutational spectrum was characterized by the presence of Asian-specific mutations c.919-2A>G and c.2027T>A (p.Leu676Gln), predominantly found in Tuvinian patients, and c.2168A>G (p.His723Arg), which was only detected in Altaian patients. In addition, a novel pathogenic variant c.1545T>G (p.Phe515Leu) was found with high frequency in Tuvinian patients. Overall, based on the findings of this study and our previous research, we were able to uncover the genetic causes of HL in 50.5% of Tuvinian patients and 34.5% of Altaian patients.

scholarly journals Analysis of the mutational spectrum of the SLC26A4 gene and its contribution to the etiology of inherited hearing loss in the indigenous population of Southern Siberia

2020 ◽  
pp. 43-45
Author(s):  
В.Ю. Данильченко ◽  
М.В. Зыцарь ◽  
Е.А. Маслова ◽  
М.С. Бады-Хоо ◽  
И.В. Морозов ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Unknown Etiology ◽  
Southern Siberia ◽  
Pathogenic Variants ◽  
Slc26a4 Gene ◽  
Wide Range ◽  
Polymorphic Variants ◽  
Tyva Republic

Мутации в гене SLC26A4 являются частой причиной потери слуха во многих регионах мира. В работе приводятся результаты молекулярно-генетического анализа (с использованием секвенирования по Сэнгеру) последовательности гена SLC26A4, впервые проведенного в выборке пациентов с потерей слуха неустановленной этиологии (n=232) из Республик Тыва и Алтай. Установлены контрастные различия патогенетического вклада мутаций в гене SLC26A4 в этиологию нарушения слуха у коренных жителей этих географически близких регионов: 28,2% - для тувинцев и 4,3% - для алтайцев. Выявлены как уже известные, так и новые патогенные варианты, а также широкий спектр полиморфных вариантов гена SLC26A4. Mutations in the SLC26A4 gene are a common cause of hearing loss in many regions of the world. This paper presents the results of molecular genetic analysis (by Sanger sequencing) of the SLC26A4 sequence, first performed in the sample of patients with hearing loss of unknown etiology (n=232) from the Tyva Republic and the Altai Republic. Contrast differences of the pathogenic contribution of SLC26A4 mutations to the etiology of hearing impairment were revealed in the indigenous peoples of these geographically close regions: 28.2% for Tuvinians and 4.3% for Altaians. Both known and novel pathogenic variants as well as a wide range of polymorphic variants were found in the SLC26A4 gene sequence.

scholarly journals Racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing for sensorineural hearing loss

2021 ◽  
Author(s):  
Michelle M. Florentine ◽  
Stephanie L. Rouse ◽  
Jihyun Stephans ◽  
David Conrad ◽  
Josephine Czechowicz ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Genetic Testing ◽  
Sensorineural Hearing Loss ◽  
Genetic Diagnosis ◽  
Ethnic Disparities ◽  
Black Children ◽  
Sensorineural Hearing ◽  
Unknown Etiology ◽  
Racial And Ethnic Disparities ◽  
Diagnostic Efficacy

AbstractUnderstanding racial and ethnic disparities in diagnostic rates of genetic testing is critical for health equity. We sought to understand the extent and cause of racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing (CGT) for sensorineural hearing loss (SNHL). We performed a retrospective cohort study at two tertiary children’s hospitals on a diverse cohort of 240 consecutive pediatric patients (76% publicly insured, 82% non-White) with SNHL of unknown etiology who underwent CGT. Definite and possible genetic diagnoses were assigned for each patient, representing the likelihood of a genetic cause of hearing loss. Associations between diagnostic rates were examined. 3.8 ± 2.1 variants were detected per patient; this frequency did not vary between White/Asian and Hispanic/Black cohorts. Overall, 82% of variants were variants of uncertain significance (VUS). Compared with White and Asian subjects, variants identified among Hispanic and Black children were less likely to be classified as pathogenic/likely pathogenic (15% vs. 24%, p < 0.001), and Hispanic and Black children were less likely to have a definite genetic diagnosis (10% vs. 37%, p < 0.001). The adjusted odds ratio for definite genetic diagnosis in Black and Hispanic children compared with White and Asian children was 0.19. Expanding genetic diagnostic criteria to include predicted deleterious VUSs reduced these disparities between White/Asian and Hispanic/Black children, with comparable molecular diagnostic rates (41% vs. 38%, p = 0.72). However, in silico predictions are insufficiently valid for clinical use. Increased inclusion of underrepresented groups in genetic hearing-loss studies to clinically validate these variants is necessary to reduce racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing.

Genetic diagnosis and cochlear implantation for patients with nonsyndromic hearing loss and enlarged vestibular aqueduct

2012 ◽  
Vol 126 (4) ◽  
pp. 349-355 ◽  
Author(s):  
R Lai ◽  
P Hu ◽  
F Zhu ◽  
G Zhu ◽  
R Vivero ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cochlear Implantation ◽  
Genetic Diagnosis ◽  
Chinese Patients ◽  
Nonsyndromic Hearing Loss ◽  
Novel Mutations ◽  
Enlarged Vestibular Aqueduct ◽  
Asian Populations ◽  
Vestibular Aqueduct ◽  
Genetic Examination

AbstractObjective:To review the genotype and cochlear implantation outcome of patients with nonsyndromic hearing loss and enlarged vestibular aqueduct.Methods:Twenty-one Chinese children with nonsyndromic hearing loss and enlarged vestibular aqueduct underwent genetic examination. A DNA microarray was used to screen for the IVS7-2A>G and H723R mutations. Any DNA samples with one or none of the two mutant alleles were sequenced to detect other mutations in the SLC26A4 and FOXI1 genes.Results:Twelve SLC26A4 mutations were detected, including three novel mutations. The most common mutations detected were IVS7-2A>G and H723R. Twelve patients received cochlear implants, and subsequently demonstrated excellent speech perception.Conclusion:Three novel mutations were detected in Chinese patients with nonsyndromic hearing loss and enlarged vestibular aqueduct. The SLC26A4 mutation spectrum in the Chinese population is similar to that in other East Asian populations. Cochlear implantation is a safe and effective treatment in patients with enlarged vestibular aqueduct.

scholarly journals Pendred Syndrome in a large consanguineous Brazilian family caused by a homozygous mutation in the SLC26A4 gene

2008 ◽  
Vol 52 (8) ◽  
pp. 1296-1303 ◽  
Author(s):  
Adriana Lofrano-Porto ◽  
Gustavo B. Barra ◽  
Paula P. Nascimento ◽  
Patrícia G. G. Costa ◽  
Érica C. Garcia ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phenotypic Variability ◽  
Sensorineural Deafness ◽  
Molecular Characteristics ◽  
Homozygous Mutation ◽  
Thyroid Function Tests ◽  
Pendred Syndrome ◽  
Slc26a4 Gene ◽  
Organification Defect ◽  
Temporal Bones

Pendred Syndrome (PS) is an autossomal recessive disorder characterized by sensorineural deafness, goiter and iodide organification defect. The hearing loss is associated with inner ear abnormalities, ranging from an isolated enlarged vestibular aqueduct (EVA) to a typical coclear dysplasia. Mutations in the gene that encodes pendrin (SLC26A4), a chloride/iodide transporter, have been shown to be associated with PS. We describe the clinical and molecular characteristics of a large consanguineous family harboring a mutation in the SLC26A4 gene. The proband was a 26-year-old deaf Brazilian woman who presented a bulky multinodular goiter and hypothyroidism since puberty. Five other siblings were deaf: one brother had a similar phenotype, three siblings also had goiters but normal thyroid function tests, and one brother had only a subtle thyroid enlargement. Other 4 siblings had no thyroid or hearing disorder. Parents were first degree cousins and had normal hearing. The mother was healthy, except for subclinical hypothyroidism; the father was deceased. A perchlorate test in the proband showed a discharge of 21% of the incorporated iodide 2h after the administration of 1g of KClO4. Audiological examinations showed profound hearing loss in all deaf subjects; CT and MRI of the temporal bones showed EVA in all of them. Genomic DNA was isolated from whole blood, from the 6 affected and 4 unaffected siblings, the mother and control. The coding region of the PDS gene (exons 2-21), including exon/intron boundaries, were amplified by PCR and sequenced. A single base-pair (T) deletion at position 1197 of exon 10 was detected in homozygous state in the 6 deaf siblings. The mother and 2 unaffected siblings were heterozygous for this mutation, which has been described by Everett et al. The 1197delT mutation is predicted to result in a frameshift and a truncated protein. The existence of PS phenocopies and intrafamilial phenotypic variability are well documented. The definite diagnosis requires molecular analysis. Our study illustrates the value and challenges of mutational analysis in selected patients with PS.

scholarly journals Intrafamilial Variability of the Deafness and Goiter Phenotype in Pendred Syndrome Caused by a T416P Mutation in the SLC26A4 Gene

2004 ◽  
Vol 89 (11) ◽  
pp. 5347-5351 ◽  
Author(s):  
Ulrike Napiontek ◽  
Guntram Borck ◽  
Wiebke Müller-Forell ◽  
Nicole Pfarr ◽  
Andrea Bohnert ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Distinct Type ◽  
Pendred Syndrome ◽  
Phenotypic Differences ◽  
Vestibular Aqueduct ◽  
Slc26a4 Gene ◽  
Sequence Variations ◽  
Ear Malformations ◽  
Long Term Follow Up ◽  
Bilateral Sensorineural Hearing Loss

Abstract Pendred syndrome (PS) is the most common cause of syndromic deafness, accounting for more than 5% of all autosomal-recessive hearing loss cases. It is characterized by bilateral sensorineural hearing loss and by goiter with or without hypothyroidism. Mutations in the SLC26A4 gene cause both classical PS and deafness associated with an enlarged vestibular aqueduct without goiter. To investigate a possible genotype-phenotype correlation in PS, we performed a detailed clinical and genetic study in three adult German sibs with typical PS caused by a common homozygous SLC26A4 mutation, T416P. An audiological long-term follow-up of 23 yr showed that the mutation T416P is associated with a distinct type of hearing loss in each of the three sibs: moderate-to-profound progressive deafness, profound nonprogressive deafness, and a milder but more rapidly progressing form. We show that these phenotypic differences are not caused by either different degrees of inner ear malformations or sequence variations in the GJB2/connexin 26 gene. Because the thyroid phenotype was also highly variable within the family, with thyroid sizes ranging from normal to large goiters requiring thyroidectomy, this study leads to the conclusion that other environmental and/or genetic factors have an impact on the PS phenotype.

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 &gt; 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 &gt; 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 &gt; 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.

Genetic Alterations in Pendrin (SLC26A4) Gene in Adult Hypothyroid Patients

2017 ◽  
Vol 49 (09) ◽  
pp. 680-686 ◽  
Author(s):  
Sourav Mukherjee ◽  
Manalee Guha ◽  
Bidisha Adhikary ◽  
Biswabandhu Bankura ◽  
Pubali Mitra ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Patient Population ◽  
Specific Activity ◽  
Genetic Alterations ◽  
Heterozygous State ◽  
Pendred Syndrome ◽  
Single Nucleotide Variants ◽  
Slc26a4 Gene ◽  
First Time ◽  
Hypothyroid Patients

AbstractCurrent study was aimed to screen the SLC26A4 gene in 127 nonautoimmune and noncongenital hypothyroid patients, who were under optimal iodine nutrition and devoid of any characteristics of Pendred syndrome from eastern part of Indian population. 8 single nucleotide variants/mutations were identified in heterozygous state in 20% patient population, which include 1 novel nonsynonymous (p.C18S), 1 novel intronic (g.942C>A), 3 known nonsynonymous (p.S23X, p.V239D, and p.I455F), and 3 known intronic (g.23034G>T, g.29641C>G, and g.33893T>C) variants. Only g.23034G>T was noted also in homozygous state in 2% patient population. However, Controls exhibited only the variations g.23034G>T and p.I455F. Therefore, present study reports for the first time that the observed novel variants in pendrin gene might be linked with autoimmune negative hypothyroidism, without any characteristics of Pendred syndrome and/or congenital hypothyroidism. While, all observed known variants/mutations were reported with either Pendred syndrome and/or congenital hypothyroidism earlier, but never with nonautoimmune adult hypothyroidism solely. Thereby, the absence of any features of Pendred syndrome and/or congenital hypothyroidism in patients with observed known nonsynonymous variants/mutations may be due to either heterozygous state of each variant or differential domain specific activity of ions trafficking in the respective organ. The analysis of amino acid change at least for p.C18S, p.S23X, and p.V239D in correlation with phenotypic characteristics of respective patients might assume a possible effect on protein structure and function. Altogether, we report for the first time that genetical variations in SLC26A4 gene could play an important role in development of nonautoimmune adult hypothyroidism.

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.

Sign in / Sign up

Export Citation Format

Share Document