Publications by authors named "Tatsuo Matsunaga"

101 Publications

Effects on cervical vestibular-evoked myogenic potentials of four clinically used head and neck measurement positions in healthy subjects.

Acta Otolaryngol 2021 Aug 27;141(8):729-735. Epub 2021 Jul 27.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Background: The most reliable head and neck position for cervical vestibular-evoked myogenic potentials (cVEMPs) measurements yet to be determined.

Aims/objectives: To assess how four body positions used during clinical recordings of cVEMPs affect cVEMP parameters.

Material And Method: cVEMPs of 10 healthy subjects (26-50 years old) were recorded in four body positions: sitting/head rotated; supine/head rotated; semi-recumbent/head rotated and elevated; supine/head elevated.

Results: Mean background sternocleidomastoid muscle (SCM) electrical activity was significantly higher in positions C and D than in positions A and B. The latencies of p13 and n23 differed significantly among the four positions. Raw p13-n23 complex amplitude was significantly greater in positions C and D than in A and B. These differences were reduced when amplitudes were corrected by SCM activity. For positions A and B, one and two subjects, respectively, had an abnormal raw asymmetry ratio (AR). After correction, all subjects had normal ARs in all positions.

Conclusions And Significance: Body positions in which the head is elevated produce a quicker and larger cVEMP response compared to positions in which the head is not elevated. The difference in ARs among positions can be ignored as long as the correction is made.
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http://dx.doi.org/10.1080/00016489.2021.1943520DOI Listing
August 2021

Investigation of the hearing levels of siblings affected by a single GJB2 variant: Possibility of genetic modifiers.

Int J Pediatr Otorhinolaryngol 2021 Oct 12;149:110840. Epub 2021 Jul 12.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan; Medical Genetics Center, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan. Electronic address:

Objective: Variants in GJB2 can cause autosomal recessive deafness (DFNB1). There is evidence for genotype-phenotype correlations of GJB2 variants; however, several genotypes can cause varying levels of hearing loss likely attributable to differences in genetic or environmental background. As siblings share approximately 50% of their genetic background and usually have a common environmental background, analysis of phenotypes of siblings with a specific GJB2 variant may reveal factors relevant to phenotypic variation. There have been no previous analyses of differences in hearing among siblings carrying a single GJB2 genotype. Here, we investigated hearing differences between siblings with a single GJB2 variant, which can cause various levels of hearing loss.

Methods: We examined hearing levels in 16 pairs of siblings homozygous for the c.235delC variant of GJB2. Differences in hearing acuity between sibling pairs were detected by auditory evaluation.

Results: Average differences in acoustic threshold >30 dB were observed between five pairs of siblings, whereas the remaining 11 pairs had average threshold values within approximately 10 dB of one another. Hearing loss varied from moderate to profound.

Conclusion: Our results indicate that auditory acuity associated with homozygosity for GJB2 c.235delC can vary in degree; however, in approximately 70% of younger siblings, it was approximately the same as that in the first child, despite a diverse spectrum of hearing loss among different families. These results suggest that differences in genetic background may modify the phenotype associated with homozygous GJB2 c.235delC.
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http://dx.doi.org/10.1016/j.ijporl.2021.110840DOI Listing
October 2021

Metacarpophalangeal pattern profile analysis for a 3-month-old infant with Feingold syndrome 2.

Am J Med Genet A 2021 03 27;185(3):952-954. Epub 2020 Dec 27.

Department of Pediatrics, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

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http://dx.doi.org/10.1002/ajmg.a.62038DOI Listing
March 2021

Clinical genetics, practice, and research of deafblindness: From uncollected experiences to the national registry in Japan.

Authors:
Tatsuo Matsunaga

Auris Nasus Larynx 2021 Apr 26;48(2):185-193. Epub 2020 Aug 26.

Department of Otolaryngology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan; Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Japan; Medical Genetics Center, National Hospital Organization Tokyo Medical Center, Japan. Electronic address:

Deafblindness is a condition of combined vision and hearing loss that is extremely rare in children and young adults, as well as being a highly heterogeneous condition, with over 70 specific etiologies. Due to these features, sporadic clinical experiences have not been collated, which has hampered medical progress. Genetics plays a major role in the pathogenesis of deafblindness in children and young adults, with more than 50 hereditary syndromes and disorders associated with the condition, including CHARGE, Usher, Down, Stickler, and Dandy-Walker syndromes, which are the most common. Clinical diagnosis of deafblindness is often difficult, and a significant proportion of patients are undiagnosed. No curative therapy is currently available for the majority of patients with hereditary deafblindness; however, experimental studies using animal models have shown promising results by targeting specific genes that cause vision or hearing loss. In Japan, the Rare Disease Data Registry of Japan (RADDAR-J) has been established as a national registry of rare and intractable diseases. Diseases of deafblindness have been elected as a disease category in RADDAR-J. Currently, clinical and genomic data are being collected and analyzed using this system, with the aim of generating an overview of deafblindness to improve medical practice.
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http://dx.doi.org/10.1016/j.anl.2020.08.017DOI Listing
April 2021

Single nucleotide polymorphisms in tinnitus patients exhibiting severe distress.

Sci Rep 2020 08 3;10(1):13023. Epub 2020 Aug 3.

Department of Otolaryngology, Keio University School of Medicine, Tokyo, Japan.

The association between distress caused by tinnitus and psychological factors such as depression and anxiety has been examined and reported. However, prognostic factors remain poorly understood because there are only a few reports on genetic associations. We theorized there might be an association between the grade of tinnitus distress and the genetic background related to psychological factors which might lead us to identify prognostic markers. We enrolled 138 patients who had suffered from tinnitus for over 3 months. Using Tinnitus Handicap Inventory (THI) scores, we examined the association between tinnitus distress and a genetic background related to depression or anxiety. A significant association between single nucleotide polymorphism rs131702 of the Breakpoint Cluster Region (BCR) gene and the severe THI score was identified. In addition, there was an association with the severity of the State-Trait Anxiety Inventory, an index of state anxiety severity. No association was found with the Self-Rating Depression Scale, an index of depression severity. It is reported that rs131702 of BCR in Japanese patients are related to bipolar II depression characterized by fluctuation between abnormal mood states of mania and depression. Our results indicate that rs131702 of BCR is independent of depression in this study and is, therefore, a prognostic factor unique to tinnitus. We conclude that the severity of tinnitus is associated with genes related to depression.
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http://dx.doi.org/10.1038/s41598-020-69467-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398919PMC
August 2020

Loss of imprinting of the human-specific imprinted gene causes prenatal growth retardation and dysmorphic features: implications for phenotypic overlap with Silver-Russell syndrome.

J Med Genet 2021 Jun 23;58(6):427-432. Epub 2020 Jun 23.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Background: , encoding a zinc-finger protein, is the human-specific maternally expressed imprinted gene located on 16p13.3. The parent-of-origin expression of is regulated by the :TSS-DMR, of which only the paternal allele acquires methylation during postimplantation period. Overexpression of may contribute to some of the phenotypes associated with maternal uniparental disomy of chromosome 16 (UPD(16)mat), and some patients with UPD(16)mat presenting with Silver-Russell syndrome (SRS) phenotype have recently been reported.

Methods: A 6-year-old boy presented with prenatal growth restriction, macrocephaly at birth, forehead protrusion in infancy and clinodactyly of the fifth finger. Methylation, expression, microsatellite marker, single nucleotide polymorphism array and trio whole-exome sequencing analyses were conducted.

Results: Isolated hypomethylation of the :TSS-DMR and subsequent loss of imprinting and overexpression of were confirmed in the patient. Epigenetic alterations, such as UPD including UPD(16)mat and other methylation defects, were excluded. Pathogenic sequence or copy number variants affecting his phenotypes were not identified, indicating that primary epimutation occurred postzygotically.

Conclusion: We report the first case of isolated imprinting defect, showing phenotypic overlap with SRS despite not satisfying the clinical SRS criteria. A novel imprinting disorder entity involving the imprinted domain can be speculated.
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http://dx.doi.org/10.1136/jmedgenet-2020-107019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142457PMC
June 2021

Differences in hearing levels between siblings with hearing loss caused by GJB2 mutations.

Auris Nasus Larynx 2020 Dec 15;47(6):938-942. Epub 2020 Jun 15.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan; Medical Genetics Center, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan. Electronic address:

Objective: Hearing loss caused by GJB2 mutations is inherited in an autosomal recessive manner (DFNB1); thus siblings of an affected child have a 25% chance of also being affected. Hearing loss among subsequent siblings carrying the same GJB2 mutation is a concern for parents and a frequent topic of enquiry during genetic counseling. Evidence exists for genotype-phenotype correlations of GJB2 mutations; however, no analysis of differences in hearing among siblings, in whom the common genetic background may decrease variation, has been reported. The purpose of the present study was to investigate hearing differences between siblings with identical GJB2 mutations.

Methods: We examined the hearing levels of 12 pairs of siblings; each pair had the same pathogenic GJB2 mutations. Differences in hearing acuity between sibling pairs detected by auditory evaluation.

Results: No significant correlation was detected between the average hearing levels of first and second affected siblings. Average differences in acoustic threshold >30 dB were observed between four pairs of siblings, whereas the remaining eight pairs had average threshold values within 20 dB of one another.

Conclusion: Our results indicate that auditory acuity would be expected to approximate that found in the first child in approximately 70% of subsequent children with GJB2-mediated hearing loss, whereas 30% of subsequent siblings would have average differences of >30 dB.
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http://dx.doi.org/10.1016/j.anl.2020.05.008DOI Listing
December 2020

A phase I/IIa double blind single institute trial of low dose sirolimus for Pendred syndrome/DFNB4.

Medicine (Baltimore) 2020 May;99(19):e19763

Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan.

Introduction: Pendred syndrome (PDS)/DFNB 4 is a disorder with fluctuating and progressive hearing loss, vertigo, and thyroid goiter. We identified pathophysiology of a neurodegenerative disorder in PDS patient derived cochlear cells that were induced via induced pluripotent stem cells and found sirolimus, an mTOR inhibitor, as an inhibitor of cell death with the minimum effective concentration less than 1/10 of the approved dose for other diseases. Given that there is no rational standard therapy for PDS, we planned a study to examine effects of low dose oral administration of sirolimus for the fluctuating and progressive hearing loss, and the balance disorder of PDS by daily monitor of their audio-vestibular symptoms.

Methods And Analysis: This is a phase I/IIa double blind parallel-group single institute trial in patient with PDS/DFNB4. Sixteen of outpatients with fluctuating hearing diagnosed as PDS in SLC26A4 genetic testing aged in between 7 and 50 years old at the time of consent are given either placebo or sirolimus tablet (NPC-12T). In NPC-12T placebo arm, placebo will be given for 36 weeks; in active substance arm, placebo will be given for 12 weeks and the NPC-12T for 24 weeks. Primary endpoints are safety and tolerability. The number of occurrences and types of adverse events and of side effects will be sorted by clinical symptoms and by abnormal change of clinical test results. A 2-sided 95% confidence interval of the incidence rate by respective dosing arms will be calculated using the Clopper-Pearson method. Clinical effects on audio-vestibular tests performed daily and precise physiological test at each visit will also be examined as secondary and expiratory endpoints.

Trial Registration Number: JMA-IIA00361; Pre-results.
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http://dx.doi.org/10.1097/MD.0000000000019763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220392PMC
May 2020

Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans.

PLoS Genet 2020 04 15;16(4):e1008643. Epub 2020 Apr 15.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Meguro, Tokyo, Japan.

Hereditary hearing loss is challenging to diagnose because of the heterogeneity of the causative genes. Further, some genes involved in hereditary hearing loss have yet to be identified. Using whole-exome analysis of three families with congenital, severe-to-profound hearing loss, we identified a missense variant of SLC12A2 in five affected members of one family showing a dominant inheritance mode, along with de novo splice-site and missense variants of SLC12A2 in two sporadic cases, as promising candidates associated with hearing loss. Furthermore, we detected another de novo missense variant of SLC12A2 in a sporadic case. SLC12A2 encodes Na+, K+, 2Cl- cotransporter (NKCC) 1 and plays critical roles in the homeostasis of K+-enriched endolymph. Slc12a2-deficient mice have congenital, profound deafness; however, no human variant of SLC12A2 has been reported as associated with hearing loss. All identified SLC12A2 variants mapped to exon 21 or its 3'-splice site. In vitro analysis indicated that the splice-site variant generates an exon 21-skipped SLC12A2 mRNA transcript expressed at much lower levels than the exon 21-included transcript in the cochlea, suggesting a tissue-specific role for the exon 21-encoded region in the carboy-terminal domain. In vitro functional analysis demonstrated that Cl- influx was significantly decreased in all SLC12A2 variants studied. Immunohistochemistry revealed that SLC12A2 is located on the plasma membrane of several types of cells in the cochlea, including the strial marginal cells, which are critical for endolymph homeostasis. Overall, this study suggests that variants affecting exon 21 of the SLC12A2 transcript are responsible for hereditary hearing loss in humans.
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http://dx.doi.org/10.1371/journal.pgen.1008643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159186PMC
April 2020

Clinical Profiles of DFNA11 at Diverse Stages of Development and Aging in a Large Family Identified by Linkage Analysis.

Otol Neurotol 2020 07;41(6):e663-e673

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Hypothesis: The phenotype of DFNA11 consists of specific features at diverse developmental and age stages.

Background: Only eight mutations have been identified for autosomal dominant non-syndromic hearing loss related to MYO7A (DFNA11), and the onset and progression of DFNA11 are poorly understood.

Methods: After linkage analysis and following Sanger sequencing in a family suspected to have autosomal dominant hereditary hearing loss, we analyzed the audiometric and vestibular functions and their long-term changes in the subjects carrying the variant.

Results: A reported variant of uncertain significance, NP_000251.3:p.Arg853His, in MYO7A was detected and cosegregation data of this large family provided evidence that the variant was likely pathogenic for DFNA11. Family members with the variant had no other symptoms associated with hearing loss and were confirmed to have autosomal dominant non-syndromic sensorineural hearing loss. Audiograms tended to show gently sloping configuration in childhood and flat configuration after the age of 30 years. Hearing loss at high frequencies progressed slowly, while hearing at low frequencies started to deteriorate later but progressed more rapidly. Some subjects showed partly abnormal results in the distortion products of otoacoustic emissions before the elevation of hearing thresholds. Vestibular function was within the normal range in all the subjects tested.

Conclusion: We revealed that hearing loss at high frequencies was mainly noted in early developmental stages and that thresholds increased more rapidly in the low frequency range, resulting in changes in audiometric configuration. Deterioration of distortion product otoacoustic emissions (DPOAE) before the elevation of hearing thresholds was considered as a clinical feature of DFNA11.
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http://dx.doi.org/10.1097/MAO.0000000000002604DOI Listing
July 2020

Autosomal dominant optic atrophy with gene mutations accompanied by auditory neuropathy and other systemic complications in a Japanese cohort.

Mol Vis 2019 5;25:559-573. Epub 2019 Oct 5.

Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Purpose: This study aimed to describe the genetic and clinical characteristics of four Japanese patients with autosomal dominant optic atrophy (DOA) accompanied by auditory neuropathy and other systemic complications (i.e., DOA-plus disease).

Methods: Four patients from four independent families underwent comprehensive ophthalmic and auditory examinations and were diagnosed with DOA-plus disease. The disease-causing gene variants in the gene were identified by direct sequencing. The genetic and clinical data of 48 DOA patients without systemic complications-that is, with simple DOA-were compared to those of DOA-plus patients.

Results: DOA-plus patients noticed a decrease in vision before the age of 14 and hearing impairment 3 to 13 years after the development of visual symptoms. Two patients had progressive external ophthalmoplegia, and one patient had vestibular dysfunction and ataxia. The DOA-plus phenotypes accounted for 13.3% (4/30) of the families with the gene mutations. Each DOA-plus patient harbored one of the monoallelic mutations in the gene: c.1334G>A, p.R445H, c.1618A>C, p.T540P, and c.892A>C, p.S298R. Missense mutations accounted for 100% (4/4) of the DOA-plus families and only 11.5% (3/26) of the families with simple DOA.

Conclusions: All the patients with the DOA-plus phenotype carried one of the missense mutations in the gene. They all had typical ocular symptoms and signs of DOA in their first or second decade, and other systemic complications-such as auditory neuropathy, vestibular dysfunction, and ataxia-followed the ocular symptoms. We should consider the occurrence of extraocular complications in cases with DOA, especially when they carry the missense mutations in the gene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798706PMC
April 2020

Systematic quantification of the anion transport function of pendrin (SLC26A4) and its disease-associated variants.

Hum Mutat 2020 01 26;41(1):316-331. Epub 2019 Oct 26.

Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Thanks to the advent of rapid DNA sequencing technology and its prevalence, many disease-associated genetic variants are rapidly identified in many genes from patient samples. However, the subsequent effort to experimentally validate and define their pathological roles is extremely slow. Consequently, the pathogenicity of most disease-associated genetic variants is solely speculated in silico, which is no longer deemed compelling. We developed an experimental approach to efficiently quantify the pathogenic effects of disease-associated genetic variants with a focus on SLC26A4, which is essential for normal inner ear function. Alterations of this gene are associated with both syndromic and nonsyndromic hereditary hearing loss with various degrees of severity. We established HEK293T-based stable cell lines that express pendrin missense variants in a doxycycline-dependent manner, and systematically determined their anion transport activities with high accuracy in a 96-well plate format using a high throughput plate reader. Our doxycycline dosage-dependent transport assay objectively distinguishes missense variants that indeed impair the function of pendrin from those that do not (functional variants). We also found that some of these putative missense variants disrupt normal messenger RNA splicing. Our comprehensive experimental approach helps determine the pathogenicity of each pendrin variant, which should guide future efforts to benefit patients.
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http://dx.doi.org/10.1002/humu.23930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930342PMC
January 2020

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.

Genet Med 2019 11 4;21(11):2442-2452. Epub 2019 Jun 4.

Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.

Purpose: Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.

Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed.

Results: The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.

Conclusion: Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
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http://dx.doi.org/10.1038/s41436-019-0535-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235630PMC
November 2019

Correction: ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs.

Genet Med 2019 Oct;21(10):2409

Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-019-0553-7DOI Listing
October 2019

A clinical and genetic study of 16 Japanese families with Waardenburg syndrome.

Gene 2019 Jul 10;704:86-90. Epub 2019 Apr 10.

Department of Otolaryngology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. Electronic address:

The purpose of this study is to profile the clinical and genetic features of Japanese Waardenburg syndrome (WS) patients and validate the W index. Sixteen Japanese WS families with congenital sensorineural hearing loss were included in the study. The inner canthal, interpupillary, and outer canthal distances (ICD, IPD, and OCD) were measured for all patients, and patients were screened for presence of PAX3, MITF, SOX10, and EDNRB mutations. The WS patients were clinically classified under the current W index as follows: 13 families with WS1, 2 families with WS2, and 1 family with WS4. In the 13 WS1 families, genetic tests found PAX3 mutations in 5 families, MITF mutations in 4 families, SOX10 mutations in 3 families, and EDNRB mutations in 1 family. 61% of clinically classified WS1 patients under the current W index conflicted with the genetic classification, which implies W index is not appropriate for Japanese population. Resetting the threshold of W index or novel index formulated with ethnicity matched samples is necessary for clinical classification which is consistent with genetic classification for WS patients with distinct ethnicity.
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http://dx.doi.org/10.1016/j.gene.2019.04.023DOI Listing
July 2019

ClinGen expert clinical validity curation of 164 hearing loss gene-disease pairs.

Genet Med 2019 10 21;21(10):2239-2247. Epub 2019 Mar 21.

Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA, USA.

Purpose: Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene-disease relationships.

Methods: The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss.

Results: The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website ( https://search.clinicalgenome.org/kb/gene-validity ).

Conclusion: This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.
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http://dx.doi.org/10.1038/s41436-019-0487-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280024PMC
October 2019

A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism.

Horm Res Paediatr 2019 8;92(1):56-63. Epub 2019 Feb 8.

Department of Pediatrics, National Hospital Organization Tokyo Medical Center, Tokyo, Japan,

Introduction: Primary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT.

Case Description: A 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the "second hit." Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history.

Conclusions: These data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.
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http://dx.doi.org/10.1159/000495800DOI Listing
April 2020

Estimating the concentration of therapeutic range using disease-specific iPS cells: Low-dose rapamycin therapy for Pendred syndrome.

Regen Ther 2019 Jun 17;10:54-63. Epub 2018 Dec 17.

Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan.

Introduction: Pendred syndrome is an autosomal-recessive disease characterized by congenital hearing loss and thyroid goiter. Previously, cell stress susceptibilities were shown to increase in patient-derived cells with intracellular aggregation using an acute cochlear cell model derived from patient-specific pluripotent stem (iPS) cells. Moreover, we showed that rapamycin can relieve cell death. However, studies regarding long-term cell survival without cell stressors that mimic the natural course of disease or the rational minimum concentration of rapamycin that prevents cell death are missing.

Methods: In this report, we first investigated the rational minimum concentration of rapamycin using patient-specific iPS cells derived-cochlear cells with three different conditions of acute stress. We next confirmed the effects of rapamycin in long-term cell survival and phenotypes by using cochlear cells derived from three different patient-derived iPS cells.

Results: We found that inner ear cells derived from Pendred syndrome patients are more vulnerable than those from healthy individuals during long-term culturing; however, this susceptibility was relieved via treatment with low-dose rapamycin. The slow progression of hearing loss in patients may be explained, in part, by the vulnerability observed in patient cells during long-term culturing. We successfully evaluated the rational minimum concentration of rapamycin for treatment of Pendred syndrome.

Conclusion: Our results suggest that low-dose rapamycin not only decreases acute symptoms but may prevent progression of hearing loss in Pendred syndrome patients.
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http://dx.doi.org/10.1016/j.reth.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299162PMC
June 2019

Elongated EABR wave latencies observed in patients with auditory neuropathy caused by mutation.

Laryngoscope Investig Otolaryngol 2018 Oct 24;3(5):388-393. Epub 2018 Sep 24.

National Institute of Sensory Organs Tokyo Japan.

Objectives: We sought to determine how the pathology altered electrically evoked auditory brainstem responses (EABRs) in patients with hearing loss by evaluating EABRs in auditory neuropathy patients with mutations comparing with various types of congenital deafness.

Methods: We included 15 patients with congenital hearing loss, grouped according to pathology: mutations (n = 4), mutations (n = 4), mutations (n = 4), or cytomegalovirus infections (n = 3). EABRs were recorded when patients underwent cochlear implantation surgery. We evaluated the latencies and amplitudes of the recorded EABRs and compared them statistically between four groups.

Results: The EABR latencies of Wave III and Wave V, and of the interval between them, were significantly longer in the mutation group than in the and mutation groups (Wave III) and in all three other groups (Wave V and Wave III-V latency); amplitudes were not significantly different between groups.

Conclusions: Our results suggest mutations cause delayed (or slowed) postsynaptic neurotransmission, although the presumed mechanism involved reduced presynaptic transmission between hair cells and spiral ganglion neurons.

Level Of Evidence: Mainly a case report.
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http://dx.doi.org/10.1002/lio2.210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209615PMC
October 2018

Gene expression dataset for whole cochlea of Macaca fascicularis.

Sci Rep 2018 10 22;8(1):15554. Epub 2018 Oct 22.

Division Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan.

Macaca fascicularis is a highly advantageous model in which to study human cochlea with regard to both evolutionary proximity and physiological similarity of the auditory system. To better understand the properties of primate cochlear function, we analyzed the genes predominantly expressed in M. fascicularis cochlea. We compared the cochlear transcripts obtained from an adult male M. fascicularis by macaque and human GeneChip microarrays with those in multiple macaque and human tissues or cells and identified 344 genes with expression levels more than 2-fold greater than in the other tissues. These "cochlear signature genes" included 35 genes responsible for syndromic or nonsyndromic hereditary hearing loss. Gene set enrichment analysis revealed groups of genes categorized as "ear development" and "ear morphogenesis" in the top 20 gene ontology categories in the macaque and human arrays, respectively. This dataset will facilitate both the study of genes that contribute to primate cochlear function and provide insight to discover novel genes associated with hereditary hearing loss that have yet to be established using animal models.
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http://dx.doi.org/10.1038/s41598-018-33985-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197234PMC
October 2018

Publisher Correction: IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis.

Sci Rep 2018 Jul 4;8(1):10367. Epub 2018 Jul 4.

Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-28698-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030171PMC
July 2018

A case of auditory neuropathy revealed by OTOF gene mutation analysis in a junior high school girl.

J Otol 2017 Dec 15;12(4):202-206. Epub 2017 Jul 15.

National Institute of Sensory Organs, Tokyo Medical Center, Japan.

Objective: Congenital auditory neuropathy (AN) affects hearing and speech development. The degree of hearing difficulty in congenital AN varies as a function of pathology at the inner ear hair cell (IHC) synapses or the auditory nerve. We report a case of a Chinese girl with AN revealed by OTOF (otoferlin) gene mutation analysis who had only a mild hearing loss.

Patient: A 13-year-old Chinese girl was diagnosed as having congenital AN on the basis of OTOF gene mutation analysis. She manifest a mild sensorineural hearing loss with 50% maximum monosyllable speech discrimination rate, normal DPOAEs (distortion product otoacoustic emissions) beyond ambient noise levels, only SPs (summating potentials) evoked during ECoG (electrocochleography) and absent ABRs (auditory evoked brainstem responses) bilaterally to clicks presented at 100 dBnHL. She was able to effectively communicate with others by speech reading owing to her mild hearing loss. Moreover, bilateral hearing aids helped her to communicate.

Conclusions: Our patient was demonstrated to have a mutation on the OTOF gene. Nevertheless, she was able to communicate using auditory visual speech reading in spite of a mild auditory threshold elevation probably due to partial pathology at the IHC synapses or in the auditory nerve.
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http://dx.doi.org/10.1016/j.joto.2017.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002630PMC
December 2017

Response to "infantile-onset deafness in m.7445A>G carriers may be multicausal".

Int J Pediatr Otorhinolaryngol 2018 08 14;111:194. Epub 2018 Jun 14.

Center for Medical Genetics and Division of Metabolism, Chiba Children's Hospital, 579-1 Hetacho, Midori-ku, Chiba, Chiba, 266-0007, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.ijporl.2018.06.023DOI Listing
August 2018

A case report of reversible generalized seizures in a patient with Waardenburg syndrome associated with a novel nonsense mutation in the penultimate exon of SOX10.

BMC Pediatr 2018 05 23;18(1):171. Epub 2018 May 23.

Department of Otolaryngology, National Center for Child Health and Development, Tokyo, Japan.

Background: Waardenburg syndrome type 1 (WS1) can be distinguished from Waardenburg syndrome type 2 (WS2) by the presence of dystopia canthorum. About 96% of WS1 are due to PAX3 mutations, and SOX10 mutations have been reported in 15% of WS2.

Case Presentation: This report describes a patient with WS1 who harbored a novel SOX10 nonsense mutation (c.652G > T, p.G218*) in exon 3 which is the penultimate exon. The patient had mild prodromal neurological symptoms that were followed by severe attacks of generalized seizures associated with delayed myelination of the brain. The immature myelination recovered later and the neurological symptoms could be improved. This is the first truncating mutation in exon 3 of SOX10 that is associated with neurological symptoms in Waardenburg syndrome. Previous studies reported that the neurological symptoms that associate with WS are congenital and irreversible. These findings suggest that the reversible neurological phenotype may be associated with the nonsense mutation in exon 3 of SOX10.

Conclusions: When patients of WS show mild prodromal neurological symptoms, the clinician should be aware of the possibility that severe attacks of generalized seizures may follow, which may be associated with the truncating mutation in exon 3 of SOX10.
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http://dx.doi.org/10.1186/s12887-018-1139-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966879PMC
May 2018

Deterioration in Distortion Product Otoacoustic Emissions in Auditory Neuropathy Patients With Distinct Clinical and Genetic Backgrounds.

Ear Hear 2019 Jan/Feb;40(1):184-191

Division of Hearing and Balance Research, National Institute for Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Objectives: Auditory neuropathy (AN) is a clinical disorder characterized by the absence of auditory brainstem response and presence of otoacoustic emissions. A gradual loss of otoacoustic emissions has been reported for some cases of AN. Such cases could be diagnosed as cochlear hearing loss and lead to misunderstanding of the pathology when patients first visit clinics after the loss of otoacoustic emissions. The purpose of this study was to investigate the time course of changes in distortion product otoacoustic emissions (DPOAEs) in association with patients' genetic and clinical backgrounds, including the use of hearing aids.

Design: DPOAE measurements from 31 patients with AN were assessed. Genetic analyses for GJB2, OTOF, and mitochondrial m.1555A> G and m.3243A> G mutations were conducted for all cases, and the analyses for CDH23 and OPA1 were conducted for the selected cases. Patients who were younger than 10 years of age at the time of AN diagnosis were designated as the pediatric AN group (22 cases), and those who were 18 years of age or older were designated as the adult AN group (9 cases). DPOAE was measured at least twice in all patients. The response rate for DPOAEs was defined and analyzed.

Results: The pediatric AN group comprised 10 patients with OTOF mutations, 1 with GJB2 mutations, 1 with OPA1 mutation, and 10 with indefinite causes. Twelve ears (27%) showed no change in DPOAE, 20 ears (46%) showed a decrease in DPOAE, and 12 ears (27%) lost DPOAE. Loss of DPOAE occurred in one ear (2%) at 0 years of age and four ears (9%) at 1 year of age. The time courses of DPOAEs in patients with OTOF mutations were divided into those with early loss and those with no change, indicating that the mechanism for deterioration of DPOAEs includes not only the OTOF mutations but also other common modifier factors. Most, but not all, AN patients who used hearing aids showed deterioration of DPOAEs after the start of using hearing aids. A few AN patients also showed deterioration of DPOAEs before using hearing aids. The adult AN group comprised 2 patients with OPA1 mutations, 2 with OTOF mutations, and 5 with indefinite causes. Four ears (22%) showed no change in DPOAE, 13 ears (72%) showed a decrease, and one ear (6%) showed a loss of DPOAE. Although the ratio of DPOAE decrease was higher in the adult AN group than in the pediatric AN group, the ratio of DPOAE loss was lower in the adult AN group. DPOAE was not lost in all four ears with OPA1 mutations and in all four ears with OTOF mutations in the adult group.

Conclusions: DPOAE was decreased or lost in approximately 70% of pediatric and about 80% of adult AN patients. Eleven percent of pediatric AN patients lost DPOAEs by 1 year of age. Genetic factors were thought to have influenced the time course of DPOAEs in the pediatric AN group. In most adult AN patients, DPOAE was rarely lost regardless of the genetic cause.
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http://dx.doi.org/10.1097/AUD.0000000000000586DOI Listing
April 2019

IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis.

Sci Rep 2018 04 4;8(1):5608. Epub 2018 Apr 4.

Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Insertions and deletions (indels) have been implicated in dozens of human diseases through the radical alteration of gene function by short frameshift indels as well as long indels. However, the accurate detection of these indels from next-generation sequencing data is still challenging. This is particularly true for intermediate-size indels (≥50 bp), due to the short DNA sequencing reads. Here, we developed a new method that predicts intermediate-size indels using BWA soft-clipped fragments (unmatched fragments in partially mapped reads) and unmapped reads. We report the performance comparison of our method, GATK, PINDEL and ScanIndel, using whole exome sequencing data from the same samples. False positive and false negative counts were determined through Sanger sequencing of all predicted indels across these four methods. The harmonic mean of the recall and precision, F-measure, was used to measure the performance of each method. Our method achieved the highest F-measure of 0.84 in one sample, compared to 0.56 for GATK, 0.52 for PINDEL and 0.46 for ScanIndel. Similar results were obtained in additional samples, demonstrating that our method was superior to the other methods for detecting intermediate-size indels. We believe that this methodology will contribute to the discovery of intermediate-size indels associated with human disease.
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http://dx.doi.org/10.1038/s41598-018-23978-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884821PMC
April 2018

High-level heteroplasmy for the m.7445A>G mitochondrial DNA mutation can cause progressive sensorineural hearing loss in infancy.

Int J Pediatr Otorhinolaryngol 2018 May 27;108:125-131. Epub 2018 Feb 27.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan; Medical Genetics Center, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan. Electronic address:

Objective: Hearing loss caused by mutation of mitochondrial DNA typically develops in late childhood or early adulthood, but rarely in infancy. We report the investigation of a patient to determine the cause of his early onset hearing loss.

Materials And Methods: The proband was a boy aged 1 year and 2 months at presentation. Newborn hearing screening test by automated auditory brainstem response generated "pass" results for both ears. His reaction to sound deteriorated by 9 months. Average pure tone threshold at 0.5, 1, and 2 kHz was 55 dB by conditioned orientation response audiometry. His father had congenital hearing loss, and his mother had progressive hearing loss since childhood. Invader assays and Sanger sequencing were performed to investigate genetic causes of the hearing loss in the proband, and heteroplasmy was assessed by PCR-restriction fragment length polymorphism, Sanger sequencing, and pyrosequencing. Additionally, mitochondrial function was evaluated by measurement of the oxygen consumption rate of patient skin fibroblasts.

Results: An m.7445A > G mitochondrial DNA mutation and a heterozygous c.235delC (p.L79Cfs*3) mutation of GJB2 were detected in the proband. His mother carried the m.7445A > G mitochondrial DNA mutation, and his father was a compound heterozygote for GJB2 mutations (c.[235delC]; [134G > A; 408C > A]). Tissue samples from both the proband and his mother exhibited a high degree of heteroplasmy. Fibroblasts from the proband exhibited markedly reduced oxygen consumption rates. These data indicate that the proband had impaired mitochondrial function, resulting in hearing loss.

Conclusion: This research demonstrates that hearing loss in a proband who presented in infancy and that of his mother resulted from a high level of heteroplasmy for the m.7445A > G mitochondrial DNA mutation, indicating that this alteration can cause hearing loss in infancy.
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http://dx.doi.org/10.1016/j.ijporl.2018.02.037DOI Listing
May 2018

Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome.

J Hum Genet 2018 May 2;63(5):647-656. Epub 2018 Mar 2.

Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchiogenic anomalies, hearing loss, and renal anomalies. The aim of this study was to reveal the clinical phenotypes and their causative genes in Japanese BOR patients. Patients clinically diagnosed with BOR syndrome were analyzed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA), array-based comparative genomic hybridization (aCGH), and next-generation sequencing (NGS). We identified the causative genes in 38/51 patients from 26/36 families; EYA1 aberrations were identified in 22 families, SALL1 mutations were identified in two families, and SIX1 mutations and a 22q partial tetrasomy were identified in one family each. All patients identified with causative genes suffered from hearing loss. Second branchial arch anomalies, including a cervical fistula or cyst, preauricular pits, and renal anomalies, were frequently identified (>60%) in patients with EYA1 aberrations. Renal hypodysplasia or unknown-cause renal insufficiency was identified in more than half of patients with EYA1 aberrations. Even within the same family, renal phenotypes often varied substantially. In addition to direct sequencing, MLPA and NGS were useful for the genetic analysis of BOR patients.
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http://dx.doi.org/10.1038/s10038-018-0429-8DOI Listing
May 2018

Spontaneous intramural duodenal hematoma as the manifestation of Noonan syndrome.

Am J Med Genet A 2018 02 11;176(2):496-498. Epub 2017 Dec 11.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1002/ajmg.a.38556DOI Listing
February 2018

Prevalence of TECTA mutation in patients with mid-frequency sensorineural hearing loss.

Orphanet J Rare Dis 2017 09 25;12(1):157. Epub 2017 Sep 25.

Department of Otolaryngology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo, 152-8902, Japan.

Background: To date, 102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features. Four genes have been reported as causative for mid-frequency sensorineural hearing loss (MFSNHL), among which TECTA is the most frequently reported; however, the prevalence of TECTA mutations is unknown. To elucidate the prevalence of TECTA mutation in MFSNHL and clarify genotype-phenotype correlations, we analyzed the genetic and clinical features of patients with MFSNHL.

Methods: Subjects with bilateral non-syndromic hearing loss were prescreened for GJB2 and m.1555A > G and m.3243A > G mitochondrial DNA mutations, and patients with inner ear malformations were excluded. We selected MFSNHL patients whose audiograms met the U-shaped criterion proposed by the GENDEAF study group, along with those with shallow U-shaped audiograms, for TECTA analysis. All TECTA exons were analyzed by Sanger sequencing. Novel missense variants were classified as possibly pathogenic, non-pathogenic, and variants of uncertain significance, based on genetic data. To evaluate novel possibly pathogenic variants, we predicted changes in protein structure by molecular modeling.

Results: Pathogenic and possibly pathogenic variants of TECTA were found in 4 (6.0%) of 67 patients with MFSNHL. In patients with U-shaped audiograms, none (0%) of 21 had pathogenic or possibly pathogenic variants. In patients with shallow U-shaped audiograms, four (8.7%) of 46 had pathogenic or possibly pathogenic variants. Two novel possibly pathogenic variants were identified and two previously reported mutations were considered as variant of unknown significance. The clinical features of patients with pathogenic and possibly pathogenic variants were consistent with those in previous studies. Pathogenic or possibly pathogenic variants were identified in 3 of 23 families (13.0%) which have the family histories compatible with autosomal dominant and 1 of 44 families (2.3%) which have the family histories compatible with sporadic or autosomal recessive.

Conclusions: TECTA mutations were identified in 6.0% of MFSNHL. These mutations were more frequent in patients with shallow U-shaped audiograms than those with U-shaped audiograms, and in families which have the family histories compatible with autosomal dominant than those with the family histories compatible with sporadic or autosomal recessive.
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http://dx.doi.org/10.1186/s13023-017-0708-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613382PMC
September 2017
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