Identification of a Novel Frameshift Mutation in the TECTA Gene in an Iranian Family With Autosomal Nonsyndromic Hearing Loss

Hearing loss (HL) is one of the most frequent birth defects, and genetic factors contribute to the pathogenesis of the disorder in about half of the patients. In the present study, we performed whole-exome sequencing (WES) based on Next-generation sequencing (NGS) in an Iranian family with hereditary HL. Then, Sanger sequencing was used to verify the segregation of the variant recognized in affected family members. A novel homozygous frameshift variation, c.649-650insC, in TECTA was found in the family, which might lead to a truncated TECTA protein (p. Asn218Gln fsX31). Our findings propose that the homozygous TECTA-p.N218QfsX31 mutation is the pathogenic variant for ARNSHL. To the best of our knowledge, this mutation has not been described in patients with the HL phenotype and so far has not to be reported in any of the mutation databases. Our data expand the spectrum of mutations in the TECTA gene in nonsyndromic hearing loss.

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Whole-exome sequencing and its impact in hereditary hearing loss

Genetics Research ◽

10.1017/s001667231500004x ◽

2015 ◽

Vol 97 ◽

Cited By ~ 28

Author(s):

TAHIR ATIK ◽

GUNEY BADEMCI ◽

OSCAR DIAZ-HORTA ◽

SUSAN H. BLANTON ◽

MUSTAFA TEKIN

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hereditary Deafness ◽

Whole Exome ◽

Human Genes ◽

Genetic Revolution ◽

Recent Developments ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

SummaryNext-generation sequencing (NGS) technologies have played a central role in the genetic revolution. These technologies, especially whole-exome sequencing, have become the primary tool of geneticists to identify the causative DNA variants in Mendelian disorders, including hereditary deafness. Current research estimates that 1% of all human genes have a function in hearing. To date, mutations in over 80 genes have been reported to cause nonsyndromic hearing loss (NSHL). Strikingly, more than a quarter of all known genes related to NSHL were discovered in the past 5 years via NGS technologies. In this article, we review recent developments in the usage of NGS for hereditary deafness, with an emphasis on whole-exome sequencing.

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Gene4HL: An Integrated Genetic Database for Hearing Loss

Frontiers in Genetics ◽

10.3389/fgene.2021.773009 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shasha Huang ◽

Guihu Zhao ◽

Jie Wu ◽

Kuokuo Li ◽

Qiuquan Wang ◽

...

Keyword(s):

Hearing Loss ◽

Candidate Genes ◽

Genetic Factors ◽

Genetic Data ◽

Industrialized Countries ◽

Genetic Database ◽

Comprehensive Knowledge ◽

One Stop ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Hearing loss (HL) is one of the most common disabilities in the world. In industrialized countries, HL occurs in 1–2/1,000 newborns, and approximately 60% of HL is caused by genetic factors. Next generation sequencing (NGS) has been widely used to identify many candidate genes and variants in patients with HL, but the data are scattered in multitudinous studies. It is a challenge for scientists, clinicians, and biologists to easily obtain and analyze HL genes and variant data from these studies. Thus, we developed a one-stop database of HL-related genes and variants, Gene4HL (http://www.genemed.tech/gene4hl/), making it easy to catalog, search, browse and analyze the genetic data. Gene4HL integrates the detailed genetic and clinical data of 326 HL-related genes from 1,608 published studies, along with 62 popular genetic data sources to provide comprehensive knowledge of candidate genes and variants associated with HL. Additionally, Gene4HL supports the users to analyze their own genetic engineering network data, performs comprehensive annotation, and prioritizes candidate genes and variations using custom parameters. Thus, Gene4HL can help users explain the function of HL genes and the clinical significance of variants by correlating the genotypes and phenotypes in humans.

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A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family

Audiology and Neurotology ◽

10.1159/000502251 ◽

2019 ◽

Vol 24 (5) ◽

pp. 258-263 ◽

Cited By ~ 2

Author(s):

Mahbobeh Koohiyan ◽

Mohammad Reza Noori-Daloii ◽

Morteza Hashemzadeh-Chaleshtori ◽

Mansoor Salehi ◽

Hamidreza Abtahi ◽

...

Keyword(s):

Hearing Loss ◽

Missense Variant ◽

Pedigree Analysis ◽

Gjb2 Gene ◽

Genetic Linkage Analysis ◽

Complex Process ◽

Whole Exome ◽

The Family ◽

Iranian Family ◽

Molecular Interpretation

Background and Objectives: Hereditary hearing loss (HL) can originate from mutations in one of many genes involved in the complex process of hearing. CABP2 mutations have been reported to cause moderate HL. Here, we report the whole exome sequencing (WES) of a proband presenting with prelingual, severe HL in an Iranian family. Methods: A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 2 affected members. After excluding mutations in the GJB2 gene and 7 other most common autosomal recessive nonsyndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis in the family, WES was utilized to find the possible etiology of the disease. Results: WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant in the exon 4 of the CABP2gene meets the criteria of being pathogenic according to the American College of Medical Genetics and Genomics (ACMG) interpretation guidelines. Conclusions: Up to now, 3 mutations have been reported for the CABP2gene to cause moderate ARNSHL in different populations. Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing list of genes that exhibit phenotypic heterogeneity. Expanding our understanding of the mutational spectrum of HL genes is an important step in providing the correct clinical molecular interpretation and diagnosis for patients.

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Genetic Etiology Study of Ten Chinese Families with Nonsyndromic Hearing Loss

Neural Plasticity ◽

10.1155/2018/4920980 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Songqun Hu ◽

Feifei Sun ◽

Jie Zhang ◽

Yan Tang ◽

Jinhong Qiu ◽

...

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Chinese Population ◽

Sanger Sequencing ◽

Nonsyndromic Hearing Loss ◽

Genetic Etiology ◽

Chinese Families ◽

Pathogenic Variants ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Nonsyndromic hearing loss has been shown to have high genetic heterogeneity. In this report, we aimed to disclose the genetic causes of the subjects from the ten Chinese deaf families who did not have pathogenic common genes/mutation. Next-generation sequencing (NGS) of 142 known deafness genes was performed in the probands of ten families followed by cosegregation analysis of all family members. We identified novel pathogenic variants in six families including p.D1806E/p.R1588W, p.R964W/p.R1588W, and p.G17C/p.G1449D in CDH23; p.T584M/p.D1939N in LOXHD1; p.P1225L in MYO7A; and p.K612X in EYA4. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family. In four families, no pathogenic variants were identified. Our study provided better understanding of the mutation spectrum of hearing loss in the Chinese population.

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Differential Gene Expression in Patients With Prostate Cancer and in Patients With Parkinson Disease: an Example of Inverse Comorbidity

10.21203/rs.3.rs-289371/v1 ◽

2021 ◽

Author(s):

Pietro Pepe ◽

Simona Vetrano ◽

Rossella Cannarella ◽

Aldo E Calogero ◽

Giovanna Marchese ◽

...

Keyword(s):

Prostate Cancer ◽

Causes Of Death ◽

Genetic Factors ◽

Target Genes ◽

Lewy Bodies ◽

Control Group ◽

Healthy Donors ◽

Differential Gene ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Abstract Prostate cancer (PCa) is one of the leading causes of death in Western countries. Environmental and genetic factors play a pivotal role in PCa etiology. Timely identification of the genetic causes is useful for an early diagnosis. Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder; it is associated with the presence of Lewy bodies (LBs) and genetic factors are involved in its pathogenesis. Several studies have indicated that the expression of target genes in patients with PD is inversely related to cancer development; this phenomenon has been named “inverse comorbidity”. The present study was undertaken to evaluate whether a genetic dysregulation occurs in opposite directions in patients with PD or PCa. In the present study, next-generation sequencing (NGS) transcriptome analysis was used to assess whether a genetic dysregulation in opposite directions occurs in patients with PD or PCa. The genes SLC30A1, ADO, SRGAP2C, and TBC1D12 resulted up-regulated in patients with PD compared to healthy donors as controls and down-regulated in patients with PCa compared with the same control group. These results support the hypothesis of the presence of inverse comorbidity between PD and PCa.

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Development and Validation of a Next-Generation Sequencing Panel for Syndromic and Nonsyndromic Hearing Loss

The Journal of Applied Laboratory Medicine ◽

10.1093/jalm/jfaa021 ◽

2020 ◽

Vol 5 (3) ◽

pp. 467-479 ◽

Cited By ~ 1

Author(s):

Malinda Butz ◽

Amber McDonald ◽

Patrick A Lundquist ◽

Melanie Meyer ◽

Sean Harrington ◽

...

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Copy Number Variants ◽

Analytical Sensitivity ◽

Nonsyndromic Hearing Loss ◽

Next Generation ◽

Single Nucleotide Variants ◽

Small Indels ◽

Syndromic Hearing Loss ◽

Generation Sequencing

Abstract Background Deafness and hearing loss are common conditions that can be seen independently or as part of a syndrome and are often mediated by genetic causes. We sought to develop and validate a hereditary hearing loss panel (HHLP) to detect single nucleotide variants (SNVs), insertions and deletions (indels), and copy number variants (CNVs) in 166 genes related to nonsyndromic and syndromic hearing loss. Methods We developed a custom-capture next-generation sequencing (NGS) reagent to detect all coding regions, ±10 flanking bp, for the 166 genes related to nonsyndromic and syndromic hearing loss. Our validation consisted of testing 52 samples to establish accuracy, reproducibility, and analytical sensitivity. In addition to NGS, supplementary methods, including multiplex ligation-dependent probe amplification, long-range PCR, and Sanger sequencing, were used to ensure coverage of regions that had high complexity or homology. Results We observed 100% positive and negative percentage agreement for detection of SNVs (n = 362), small indels (1–22 bp, n = 25), and CNVs (gains, n = 8; losses, n = 17). Finally, we showed that this assay was able to detect variants with a variant allele frequency ≥20% for SNVs and indels and ≥30% to 35% for CNVs. Conclusions We validated an HHLP that detects SNVs, indels, and CNVs in 166 genes related to syndromic and nonsyndromic hearing loss. The results of this assay can be utilized to confirm a diagnosis of hearing loss and related syndromic disorders associated with known causal genes.

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Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

Genes ◽

10.3390/genes10121047 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1047 ◽

Cited By ~ 1

Author(s):

Lama Jaffal ◽

Wissam H Joumaa ◽

Alexandre Assi ◽

Charles Helou ◽

George Cherfan ◽

...

Keyword(s):

Next Generation Sequencing ◽

Usher Syndrome ◽

Bioinformatic Analysis ◽

Next Generation ◽

Novel Mutations ◽

Pathogenic Variants ◽

Whole Exome ◽

Targeted Ngs ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.

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X-Linked Hyper IgM Syndrome Manifesting as Recurrent Pneumocystis jirovecii Pneumonia: A Case Report

Journal of Tropical Pediatrics ◽

10.1093/tropej/fmaa023 ◽

2020 ◽

Vol 66 (6) ◽

pp. 648-654

Author(s):

Sai Hu Huang ◽

Xiang Ying Meng ◽

Zhen Jiang Bai ◽

Ying Li ◽

Shui Yan Wu

Keyword(s):

Severe Pneumonia ◽

Pneumocystis Jirovecii ◽

Pneumocystis Jirovecii Pneumonia ◽

Whole Exome ◽

Hyper Igm ◽

Reading Counts ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Exon 10 ◽

Gene Exon

Abstract We reported a Chinese boy with X-linked hyper IgM (XHIGM) syndrome, manifesting as recurrent and severe pneumonia caused by Pneumocystis jirovecii. His parents were healthy and unrelated. In August 2018, the 5-month-old boy manifested as cough and dyspnea, and then in July 2019, he was admitted because of the same symptoms. Immunological results of the two admissions both showed low IgG, low IgA, normal IgM and high levels of 1,3-β-D-glucan (BDG). Using next-generation sequencing (NGS), great reading counts of P. jirovecii were identified from the deep sputum in both admissions. Caspofungin combined with trimethoprim-sulfamethoxazole were used to anti-infection, and he recovered quickly. Whole-exome sequencing was performed for this family because of immune suppression, the disease-causing gene (exon 10–22 of CD40L) deletion for XHIGM syndrome was identified. NGS is beneficial for etiology diagnosis. Pneumocystis jirovecii pneumonia as an opportunistic infection could be recurrent in patients with XHIGM syndrome.

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Whole exome sequencing identifies a novel homozygous frameshift mutation in the ASPM gene, which causes microcephaly 5, primary, autosomal recessive

F1000Research ◽

10.12688/f1000research.12102.1 ◽

2017 ◽

Vol 6 ◽

pp. 2163

Author(s):

Desaraju Suresh Bhargav ◽

N. Sreedevi ◽

N. Swapna ◽

Soumya Vivek ◽

Srinivas Kovvali

Keyword(s):

Exome Sequencing ◽

Autosomal Recessive ◽

Frameshift Mutation ◽

Protein Gene ◽

Single Gene ◽

Primary Microcephaly ◽

Sequencing Technologies ◽

Whole Exome ◽

The Family ◽

Autosomal Recessive Primary Microcephaly

Microcephaly is a genetically heterogeneous disorder and is one of the frequently notable conditions in paediatric neuropathology which exists either as a single entity or in association with other co-morbidities. More than a single gene is implicated in true microcephaly and the list is growing with the recent advancements in sequencing technologies. Using massive parallel sequencing, we identified a novel frame shift insertion in the abnormal spindle-like microcephaly-associated protein gene in a client with true autosomal recessive primary microcephaly. Exome sequencing in the present case helped in identifying the true cause behind the disease, which helps in the premarital counselling for the sibling to avoid future recurrence of the disorder in the family.

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Molekulares Verstehen des Hörens – Was ändert sich für den Patienten?

Laryngo-Rhino-Otologie ◽

10.1055/s-0043-121595 ◽

2018 ◽

Vol 97 (S 01) ◽

pp. S214-S230 ◽

Cited By ~ 1

Author(s):

Tobias Moser

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Next Generation ◽

Kausale Therapie ◽

Molekulare Analyse ◽

Hidden Hearing Loss ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Eine Verbesserte

ZusammenfassungDas Innenohr und die Hörbahn mit ihren vergleichsweise geringen Zellzahlen haben sich einigen molekularen Ansätzen bislang beharrlich entzogen. Gleichzeitig vollbringt das Hören Spitzenleistungen, die sehr spezialisierte biologische Mechanismen nahelegen. Dies bedeutet einerseits, dass Analogieschlüsse zur molekularen Anatomie und Physiologie der Zellen des Hörsystems auf der Grundlage von Erkenntnissen aus molekular besser zugänglichen Systemen von beschränktem Nutzen sind. Andererseits legt eine solche Spezialisierung Gendefekte nahe, die von der Evolution toleriert wurden, weil sie nicht zur Fehlfunktion von essentiellen Körperprozessen führen. Technologische Fortschritte in der Humangenetik und der molekularen Analyse des Innenohrs im Tier bestätigen beide Annahmen und beleuchten den faszinierenden Mikrokosmos der Cochlea. Auf kleinstem Raum werden hier in konsequenter Arbeitsteilung herausragende Leistungen im Ionentransport, der Mechanotransduktion, der aktiven Zellmotilität und der synaptischen Verarbeitung erbracht. Einige der zugrundeliegenden molekularen Maschinen, z. B. das Motorprotein Prestin und das an synaptischer Fusion beteiligte Otoferlin, sind ausschließlich im Ohr aktiv. Dementsprechend führen ihre Defekte zu spezifischen nicht-syndromalen Schwerhörigkeiten, wie etwa bei der auditorischen Synaptopathie durch autosomal rezessive Mutationen im Otoferlin-Gen. Andere Mutationen, wie die den cochleären Kalium-Zyklus betreffenden, bedingen einen globalen Funktionsverlust der Cochlea. Viele genetische Defekte führen schließlich zur Degeneration des Innenohrs. Letztlich führt die molekulare Analyse sowohl beim Menschen, als auch im Tier-Innenohr aber auch zu neuen Erkenntnissen für häufige Formen der Schwerhörigkeit. So wurde der immunhistochemische Nachweis des Verlusts von Bandsynapsen der inneren Haarzellen zum Biomarker für „hidden hearing loss“ im Tiermodell. Die moderne Hochdurchsatz-Sequenzierung (sog. Next Generation Sequencing – NGS) bietet Zugang zu bislang nicht bekannten Taubheitsgenen, Mutationsspektren von bekannten Taubheitsgenen und zu einem genetischen Profil der individuellen Schwerhörigkeit, ihre Interpretation erfordert jedoch große humangenetische Expertise und umfangreiche tierexperimentelle Einsichten. Eine kausale Therapie etwa durch viralen Genersatz, der im Tier-Innenohr und bei einzelnen Formen der humanen Blindheit bereits erfolgreich ist, steht für die Schwerhörigkeit in der Klinik noch nicht zur Verfügung. Bereits jetzt ermöglichen molekulare Ansätze aber schon eine verbesserte Beratung von schwerhörigen Patienten.

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