Publications by authors named "Noriko Morimoto"

52 Publications

Direct platelet adhesion potentiates group 2 innate lymphoid cell functions.

Allergy 2021 Aug 17. Epub 2021 Aug 17.

Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.

Background: Platelets are thought to be involved in the pathophysiology of asthma, presumably through direct adhesion to inflammatory cells, including group 2 innate lymphoid cells (ILC2s). Here, we tried to elucidate the effects of platelet adhesion to ILC2s in vitro and in vivo, as well as the mechanisms involved.

Methods: Alternaria-induced ILC2-dependent airway inflammation models using wild-type and c-mpl mice were evaluated. Both purified CD41 and CD41 ILC2s were cultured with IL-2 and IL-33 to determine in vitro Type 2 (T2) cytokine production and cell proliferation. RNA-seq data of flow-cytometry-sorted CD41 and CD41 ILC2s were used to isolate ILC2-specific genes. Flow cytometry was performed to determine the expression of CD41 and adhesion-related molecules on ILC2s in both mouse and human tissues.

Results: T2 inflammation and T2 cytokine production from ILC2s were significantly reduced in the c-mpl mice compared to wild-type mice. Platelet-adherent ILC2s underwent significant proliferation and showed enhanced T2 cytokine production when exposed to IL-2 and IL-33. The functions of ILC2-specific genes were related to cell development and function. Upstream regulator analysis identified 15 molecules, that are thought to be involved in ILC2 activation. CD41 expression levels were higher in ILC2s from human PBMCs and mouse lung than in those from secondary lymphoid tissues, but they did not correlate with the P-selectin glycoprotein ligand-1 or CD24 expression level.

Conclusion: Platelets spontaneously adhere to ILC2s, probably in the peripheral blood and airways, thereby potentiating ILC2s to enhance their responses to IL-33.
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http://dx.doi.org/10.1111/all.15057DOI 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

Value of parametric indexes to identify tracheal atresia with or without fistula on fetal magnetic resonance imaging.

Pediatr Radiol 2021 May 14. Epub 2021 May 14.

Department of Radiology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan.

Background: Tracheal atresia causes some secondary changes (dilated trachea, flattened/inverted diaphragm, hyperintense and hyperinflated lungs). They can be reduced if a high airway fistula is present.

Objective: This study evaluated fetal MR images of tracheal atresia and the secondary changes, focusing on the presence of a fistula.

Materials And Methods: We assessed fetal MR images of tracheal atresia without fistula (n=4, median 26 weeks), tracheal atresia with fistula (n=4, median 33 weeks) and controls (n=30, median 32 weeks). We evaluated airway obstruction using true-positive rate in tracheal atresia and false-positive rate in controls indicating they are likely normal variants. Tracheal diameter, craniocaudal-anteroposterior ratio of the right hemidiaphragm, lung-to-liver signal intensity ratio, and cardiothoracic ratio were compared among the three groups using the Kruskal-Wallis test followed by pairwise comparison using the Mann-Whitney U test.

Results: True-positive rate was 100% in tracheal atresia, while false-positive rate was 20% in controls. The Kruskal-Wallis test showed differences among groups in craniocaudal-anteroposterior ratio and cardiothoracic ratio (P<0.001) but not in tracheal diameter (P=0.256) or lung-to-liver signal intensity ratio (P=0.082). The pairwise comparison in craniocaudal-anteroposterior ratio and cardiothoracic ratio showed differences between controls and tracheal atresia without fistula (P<0.01) and with fistula (P<0.05).

Conclusion: Fetal MRI is useful for the diagnosis of tracheal atresia, and detection of airway obstruction is essential. Lower craniocaudal-anteroposterior ratio and cardiothoracic ratio might be reliable measures even if a fistula is present.
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http://dx.doi.org/10.1007/s00247-021-05092-xDOI Listing
May 2021

Challenge for management without tracheostomy tube after laryngo-tracheal separation in children with neurological disorders.

Laryngoscope Investig Otolaryngol 2021 Apr 6;6(2):332-339. Epub 2021 Feb 6.

Department of General Pediatrics and Interdisciplinary medicine National Center for Child Health and Development Tokyo Japan.

Objectives: The present study analyzed surgical outcomes of laryngotracheal separation (LTS) in children with neurological disorders. The purpose of this study was to investigate respiratory impairment and severe complications after LTS in children, and identify the possibility of permanent tracheostomy without a tracheostomy tube as the safest respiratory management method.

Methods: Twenty-eight patients (male:female = 16:12) with neurological disorders (6 months to 32 years) who underwent LTS between January 2012 and April 2018 were reviewed. Tracheal diameter, Cobb angle, and sternocervical spine distance (SCD) were measured to assess the potential risk and possibility of removing tracheostomy tube management.

Results: Tracheostomy tube could be removed shortly after LTS in 57% (16/28). However, nine of these patients developed respiratory problems that required tracheostomy tube placement 2 years after LTS. New requirements for a tracheostomy tube as a stent were strongly correlated with SCD ( < .05, odds ratio > 1) as well as tracheal deformity.

Conclusions: Respiratory management in neurologically impaired children after LTS without a tracheostomy tube is challenging because thoracic deformity during physical growth affects tracheal disfiguration. Thoracic deformities and progression of scoliosis should be considered in respiratory management approaches in children with neurological disorders, and long-term follow-up by computed tomography is necessary.

Level Of Evidence: IV.
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http://dx.doi.org/10.1002/lio2.534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035946PMC
April 2021

A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1.

J Hum Genet 2021 Mar 15. Epub 2021 Mar 15.

Department of Genome Medicine, National Center for Child Health and Development, Setagaya, Tokyo, Japan.

Auriculocondylar syndrome (ARCND) is an autosomal monogenic disorder characterised by external ear abnormalities and micrognathia due to hypoplasia of the mandibular rami, condyle and coronoid process. Genetically, three subtypes of ARCND (ARCND1, ARCND2 and ARCND3) have been reported. To date, five pathogenic variants of GNAI3 have been reported in ARCND1 patients. Here, we report a novel variant of GNAI3 (NM_006496:c.807C>A:p.(Asn269Lys)) in a Japanese girl with micrognathia using trio-based whole exome sequencing analysis. The GNAI3 gene encodes a heterotrimeric guanine nucleotide-binding protein. The novel variant locates the guanine nucleotide-binding site, and the substitution was predicted to interfere with guanine nucleotide-binding by in silico structural analysis. Three-dimensional computer tomography scan, or cephalogram, displayed severely hypoplastic mandibular rami and fusion to the medial and lateral pterygoid plates, which have been recognised in other ARCND1 patients, but have not been described in ARCND2 and ARCND3, suggesting that these may be distinguishable features in ARCND1.
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http://dx.doi.org/10.1038/s10038-021-00915-zDOI Listing
March 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

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

The Incidence of Sleep Disordered Breathing One Week After Primary Palatoplasty: Evaluation With Overnight Pulse Oximetry.

J Craniofac Surg 2019 Jul;30(5):1565-1567

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

Background: Sleep disordered breathing (SDB) is defined as a series of disorders including snoring, obstructive sleep apnea, and hypopnea. Few studies investigated the incidence of SDB following primary palatoplasty with objective testing. The aims of this study were to elucidate the prevalence and degree of SDB approximately 1 week following primary palatoplasty with objective testing and to clarify the risk factors.

Method: A retrospective review was performed on children who underwent primary palatoplasty between April 2013 and July 2017 at National Center for Child Health and Development, Tokyo, Japan. As a national center, the authors accept many syndromic patients. The authors keep all patients after palatoplasty intubated and observe them overnight in intensive care unit to reduce the risks of respiratory events. Patients were evaluated with overnight pulse oximetry on 5 to 7 days postoperatively.

Results: Forty-four patients were included, and 30% of the patients were associated with congenital anomaly. Thirteen patients (30%) were diagnosed with SDB. None of the patients required additional treatment after the evaluation. Laryngomalacia and postoperative oxygen requirement significantly correlated with postoperative SDB.

Conclusion: Approximately one-third of the patients may be at the risk of SDB 1 week after primary palatoplasty. Patients with history of laryngomalacia or those who required oxygen support for prolonged time after primary palatoplasty should be cared for significantly high risk of postoperative SDB.
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http://dx.doi.org/10.1097/SCS.0000000000005530DOI Listing
July 2019

Induction of defense responses by extracts of spent mushroom substrates in rice.

J Pestic Sci 2019 May;44(2):89-96

Faculty of Agriculture, Tottori University.

We investigated the effect of treatment with hot water extracts from the spent mushroom substrates (SMSs) of and on the resistance of rice leaves to infection. The spraying of the SMS extracts clearly suppressed the development of lesions caused by infection. The accumulation of phytoalexins momilactones A and B, oryzalexin A, and sakuranetin was markedly induced by the spraying of extracts. The enhanced expression of defense related genes and was also found in leaves sprayed with the extracts. Treatments with the extracts also affected phytohormone levels. The levels of -(Δ-isopentenyl)adenine and -zeatin markedly increased in response to treatment, whereas the levels of salicylic and jasmonic acids were largely unchanged.
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http://dx.doi.org/10.1584/jpestics.D18-063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529750PMC
May 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

Incidence and causes of visual impairment in Japan: the first nation-wide complete enumeration survey of newly certified visually impaired individuals.

Jpn J Ophthalmol 2019 Jan 25;63(1):26-33. Epub 2018 Sep 25.

Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho Kita-ku, Okayama, Okayama, 700-8558, Japan.

Purpose: To investigate the visual impairment certification status in Japan.

Study Design: Observational cross-sectional study.

Methods: We asked all welfare offices throughout Japan to submit data concerning age, sex, causative diseases, and visual impairment grades for newly certified visually impaired individuals aged ≥ 18 years in the fiscal year of 2015. The certification was based on criteria of the Act on Welfare of Physically Disabled Persons.

Results: In total, data were collected for 12,505 newly certified visually impaired individuals. The most common age group for these individuals was 80-89 years (29.6%), followed by 70-79 (26.3%) and 60-69 (17.3%) years. The most common causative disease was glaucoma (28.6%), followed by retinitis pigmentosa (14.0%), diabetic retinopathy (12.8%), and macular degeneration (8.0%). Glaucoma was the most common causative disease in both sexes (30.2% in men and 27.0% in women). The most common impairment grade was grade 2 (31.8%), followed by grades 5 (24.3%) and grade 1 (16.1%). The number of visually impaired individuals with underlying glaucoma had increased in comparison with the number in the most recent surveys (from fiscal years 2007 to 2009), whereas the number of individuals with underlying diabetic retinopathy and macular degeneration had decreased.

Conclusion: To our knowledge, this is the first nation-wide complete enumeration survey of newly certified visually impaired individuals in Japan. These findings may contribute to administrative activities concerning medical welfare as well as educational activities for preventing visual impairment.
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http://dx.doi.org/10.1007/s10384-018-0623-4DOI Listing
January 2019

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

Induced phenylamide accumulation in response to pathogen infection and hormone treatment in rice (Oryza sativa).

Biosci Biotechnol Biochem 2018 Mar 9;82(3):407-416. Epub 2018 Feb 9.

b Faculty of Agriculture , Tottori University , Tottori , Japan.

Rice plants accumulate various specialized metabolites, including phenylamides, in response to pathogen attack. We prepared 25 phenylamides, and developed a method of analyzing them by multiple reaction monitoring with liquid chromatography coupled with tandem mass spectrometry. We analyzed phenylamides in rice leaves infected with Cochliobolus miyabeanus and Xanthomonas oryzae. The phenylamides induced included benzoyltryptamine, cinnamoyl-, p-coumaroyl-, feruloyl-, and benzoylserotonins, cinnamoyl and benzoyltyramines, feruloylagmatine, and feruloylputrescine. Some of the phenylamides exhibited antimicrobial activity against C. miyabeanus and X. oryzae, indicating that they are phytoalexins. Treatment with jasmonic acid, salicylic acid, 6-benzylaminopurine, and ethephone also induced phenylamide accumulation. The compositions of the induced amides varied depending on the plant hormone used, and cinnamoyltryptamine, cinnamoylserotonin, and cinnamoyltyramine were not induced by the plant hormones. These findings suggest that several plant hormones and additional factors are involved in phenylamide accumulation in response to pathogen infection in rice.
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http://dx.doi.org/10.1080/09168451.2018.1429889DOI Listing
March 2018

Homozygous EDNRB mutation in a patient with Waardenburg syndrome type 1.

Auris Nasus Larynx 2018 Apr 11;45(2):222-226. Epub 2017 May 11.

Division of Hearing and Balance Research, National Institute of Sensory Organ, 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: To examine and expand the genetic spectrum of Waardenburg syndrome type 1 (WS1).

Methods: Clinical features related to Waardenburg syndrome (WS) were examined in a five-year old patient. Mutation analysis of genes related to WS was performed in the proband and her parents. Molecular modeling of EDNRB and the p.R319W mutant was conducted to predict the pathogenicity of the mutation.

Results: The proband showed sensorineural hearing loss, heterochromia iridis, and dystopia canthorum, fulfilling the clinical criteria of WS1. Genetic analyses revealed that the proband had no mutation in PAX3 which has been known as the cause of WS1, but had a homozygous missense mutation (p.R319W) in endothelin receptor type B (EDNRB) gene. The asymptomatic parents had the mutation in a heterozygote state. This mutation has been previously reported in a heterozygous state in a patient with Hirschsprung's disease unaccompanied by WS, but the patient and her parents did not show any symptoms in gastrointestinal tract. Molecular modeling of EDNRB with the p.R319W mutation demonstrated reduction of the positively charged surface area in this region, which might reduce binding ability of EDNRB to G protein and lead to abnormal signal transduction underlying the WS phenotype.

Conclusions: Our findings suggested that autosomal recessive mutation in EDNRB may underlie a part of WS1 with the current diagnostic criteria, and supported that Hirschsprung's disease is a multifactorial genetic disease which requires additional factors. Further molecular analysis is necessary to elucidate the gene interaction and to reappraise the current WS classification.
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http://dx.doi.org/10.1016/j.anl.2017.03.022DOI Listing
April 2018

Sleep Duration, Snoring Prevalence, Obesity, and Behavioral Problems in a Large Cohort of Primary School Students in Japan.

Sleep 2017 Mar;40(3)

Department of Public Health, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Study Objectives: Poor or short sleep and the presence of snoring indicative of sleep-disordered breathing (SDB) have been associated with behavioral problems in school-aged children. We examined the relationship between SDB, sleep duration, obesity risk, and behavioral characteristics in Japanese elementary school students using a large-scale survey.

Methods: We conducted a cross-sectional study of children enrolled in all 46 public primary schools in Matsuyama city, Japan. The children's parents or guardians completed a questionnaire that covered sleep habits, presence of SDB risk, and behavioral characteristics.

Results: In total, 24 296 responses were received (90% response rate). After excluding incomplete responses, we analyzed complete datasets for 17 769 children. Mean sleep duration decreased with age, as did the prevalence of pediatric SDB. We found an increased risk for the presence of SDB and short sleep among overweight/obese children. With SDB or short sleep, we observed significantly increased odds of restless behaviors, fidgety behaviors, and poor concentration in school.

Conclusions: Shorter sleep duration was associated with increased risk of obesity, and in turn, obesity increased SDB risk. Both short sleep duration and SDB risk were significantly associated with behavioral problems in school.
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http://dx.doi.org/10.1093/sleep/zsw082DOI Listing
March 2017

WFS1 and GJB2 mutations in patients with bilateral low-frequency sensorineural hearing loss.

Laryngoscope 2017 09 8;127(9):E324-E329. Epub 2017 Mar 8.

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

Objective: Evaluating the prevalence of specific gene mutations associated with a certain audiometric configuration facilitates clinical assessment of patients with sensorineural hearing loss (SNHL). WFS1 is responsible for autosomal dominant nonsyndromic deafness 6/14/38 and is the most frequent genetic cause of low-frequency SNHL (LFSNHL); however, the exact prevalence of WFS1 mutations in LFSNHL is unknown. Therefore, we evaluated genetic mutations and clinical features in patients with nonsyndromic bilateral LFSNHL, focusing on the WFS1.

Study Design: Retrospective case series from 2002 to 2013 at the National Hospital Organization Tokyo Medical Center and collaborating hospitals.

Methods: WFS1, GJB2, and mitochondrial DNA mutation screening was carried out for 74 of 1,007 Japanese probands with bilateral LFSNHL.

Results: WFS1 and GJB2 mutations were identified in eight of 74 cases (10.8%). Four cases had heterozygous WFS1 mutations; one case had a heterozygous WFS1 mutation and a heterozygous GJB2 mutation; and three cases had biallelic GJB2 mutations. Three cases with WFS1 mutations were sporadic; two of them were confirmed to be caused by a de novo mutation based on the genetic analysis of their parents. In the case with mutations in both WFS1 and GJB2, a de novo mutation of WFS1 was confirmed in the proband's mother by genetic screening of the mother's parents.

Conclusion: Genetic screening focusing on LFSNHL has not been conducted. The present study first revealed the prevalence of specific gene mutations. WFS1 autosomal dominant mutations were identified even in sporadic cases. Our results also suggested a mutational hotspot in WFS1.

Level Of Evidence: 4. Laryngoscope, 127:E324-E329, 2017.
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http://dx.doi.org/10.1002/lary.26528DOI Listing
September 2017

[Tonsillectomy in Cases with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome].

Nihon Jibiinkoka Gakkai Kaiho 2017 03;120(3):209-16

The periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease, characterized, as its name suggests, by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. This syndrome is the most common cause of recurrent fever in children, however the rate of recognition of this syndrome is still low. Tonsillectomy has been suggested as an effective treatment, even though the precise, pathophysiology underlying this syndrome remains unknown. In this study, we investigated the outcomes in patients who underwent tonsillectomy. In particular, we examined the surgical outcomes and clinical features of the patients who underwent tonsillectomy. A total of 19 patients with PFAPA syndrome underwent tonsillectomy at our hospital from July 2013 to May 2016. Before the surgery, while all the patients had received medications, none showed complete resolution of the syndromes. However, of the 19 patients, 15 showed complete resolution of the syndrome immediately after the surgery. Four patients had fever even after the surgery. Three patients showed partial remission, with the frequency and duration of the episodes decreasing after the surgery. However, in one patient, the fever persisted as before the surgery. There were no significant differences in the clinical characteristics, such as the age at onset, fever episodes, associated symptoms, or age at surgery among the three groups. However, we observed a trend towards a higher frequency of a family history in patients with persistent symptoms after surgery. Tonsillectomy was highly effective against PFAPA syndrome, however, some patients failed to respond to the procedure. Therefore, it is important to carefully evaluate the risks and benefits in each case. The indications for tonsillectomy have not yet been clearly established. It is essential to continue further investigations to establish effective therapeutic strategies for this syndrome.
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March 2017

Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography.

J Pharmacol Exp Ther 2017 03 16;360(3):457-465. Epub 2016 Dec 16.

Discovery Research Laboratories I (K.M., N.M., T.N., S.K.), and Pharmaceutical Technology Laboratories (Y.Y.), ONO Pharmaceutical Co., Ltd., Osaka, and Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka (H.O., H.T.), Japan

We have previously shown that ONO-2952, a novel 18-kDa translocator protein (TSPO) antagonist, inhibits stress-induced accumulation of neurosteroids and noradrenaline release in the rat brain and alleviates the subsequent symptomatic responses with a brain TSPO occupancy of 50% or more. In this study, we measured ONO-2952 brain TSPO occupancy in conscious rhesus monkeys using positron emission tomography (PET) with C-PBR28 as ligand for translational research to clinical application. PET scans were performed after single and repeated oral administration of ONO-2952 at several dose levels for each animal, with sequential arterial blood sampling. In vitro binding studies showed that ONO-2952 potently binds to brain TSPO in monkeys with an affinity equivalent to that in rats. ONO-2952, given orally before PET scans, dose dependently decreased C-PBR28 uptake without marked brain region specificity. Results of the quantitative analysis using arterial input function revealed that TSPO occupancy after ONO-2952 single and repeated oral administration tended to increase in parallel with its plasma concentration, reaching the highest level of 100%. These findings indicate that ONO-2952 has sufficient brain distribution in primates and that ONO-2952 TSPO occupancy in humans can also be determined using PET.
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http://dx.doi.org/10.1124/jpet.116.238568DOI Listing
March 2017

Pediatric tracheostomy: Survival and long-term outcomes.

Int J Pediatr Otorhinolaryngol 2016 Oct 28;89:81-5. Epub 2016 Jul 28.

Otorhinolaryngology, National Center for Child Health and Development, Tokyo, Japan.

Objectives: The objective of this study was to investigate if there were any differences in survival and long-term outcomes between pediatric patients with and without neurological impairment who underwent tracheostomy.

Methods: A retrospective chart review of pediatric patients (age 0-15 years) who underwent tracheostomy between March 2002 and December 2013 was conducted. Patients were categorized into two groups: those who were neurologically impaired (NI) (pediatric cerebral performance category, 3-6) and those who were not neurologically impaired (NN) (pediatric cerebral performance category, 1-2). Survival rates and cumulative incidence of weaning from mechanical ventilation or decannulation were calculated using the Kaplan-Meier method.

Results: A total of 212 patients were included. Among them, 141 were categorized into NI group and 71 into NN group. Between the two groups, there were no significant differences in survival rates and cumulative incidence of weaning from mechanical ventilation. In total patients, one-year survival rate was 0.86 (95%CI 0.80-0.90) and five-year survival rate was 0.71 (0.62-0.78). One-year weaning rate was 0.58 (0.51-0.65) and five-year weaning rate was 0.66 (0.59-0.74). Decannulation rates were significantly lower in NI group than in NN group (p < 0.001). One-year and five-year decannulation rates were 0.04 (0.01-0.09) and 0.17 (0.10-0.29), respectively, in NI group, and 0.20 (0.12-0.33) and 0.54 (0.40-0.69), respectively, in NN group.

Conclusions: In children who underwent tracheostomy, the decannulation rate was lower in those with neurological impairment compared with that in those without neurological impairment. There were no significant differences in survival or ventilator weaning between the two groups.
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http://dx.doi.org/10.1016/j.ijporl.2016.07.033DOI Listing
October 2016

The auditory phenotype of children harboring mutations in the prestin gene.

Acta Otolaryngol 2016 29;136(4):397-401. Epub 2016 Jan 29.

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

Conclusion Auditory phenotypes of two children harboring prestin gene mutations were congenital or pre-lingual onset, moderate to profound, slowly progressive or non-progressive, and audiograms with either flat configuration or prominently elevated thresholds at middle and high frequencies. Objectives Despite the essential role of the prestin gene in hearing, only one mutation in two families and a missense variant in a family had been reported previously before our study reporting another family. The purpose of this study was to characterize auditory phenotypes in children recently found to harbor novel mutations in the prestin gene. Methods The subjects were two sisters with bilateral sensorineural hearing loss who were compound heterozygotes for c.209G > A (p.W70X) and c.390A > C (p.R130S) mutations in the prestin gene. Clinical history and auditory test results were collected and analyzed. Results Hearing loss was present from birth in the younger sister and occurred before 6 years of age in the elder sister. The degree of hearing loss was profound in the elder sister with little progression, and moderate in the younger sister with no progression. The audiogram of the elder sister showed prominently elevated thresholds at middle and high frequencies, while that of the younger sister demonstrated a flat configuration.
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http://dx.doi.org/10.3109/00016489.2015.1126858DOI Listing
January 2017

[A Retrospective Series of 77 Pediatric Patients with Vertigo at a National Center for Child Health and Development].

Nihon Jibiinkoka Gakkai Kaiho 2015 Jul;118(7):860-6

The evaluation and management of vertigo in children varies among institutional and medical specialties. The aim of this study was to describe the characteristics of vertigo in children presenting at a national pediatric center. Patients < 16 years old presenting with vertigo to the department of otolaryngology at a national center for child health and development from April 2004 to October 2009 were included (N = 77; 42 males and 35 females; average age, 8.7 ± 3.4 years) in this study. The most common diagnoses were vestibular migraine (VM; N = 21), benign paroxysmal vertigo (BPV; N =16), unilateral vestibulopathy (N = 12), and psychogenic vertigo (N = 8). Significant differences were observed in the frequency of the diagnoses between children aged older and younger than 7 years: BPV was most common in children < 7 years of age (p < 0.01) and VM was most common in ≥ 27 years of age (p < 0.05). Because obtaining adequate information from children for making a correct diagnosis is sometimes difficult, acquiring sufficient information from the parents is important. In addition, getting the parents to record the nystagmus during a vertigo attack with a digital camera or cellular phone can be useful because observing the nystagmus recorded on the video is helpful for making a diagnosis. Furthermore, the parents are participating in their child's care by attempting to record the attack, strengthening the relationship between the parents and the child. The incidence of psychogenic vertigo is low (less than 10%). Therefore, although physicians have recently tended to define the disorder as psychogenic when no objective abnormality is found in a patient, making a diagnosis of psychogenic vertigo is not recommended. Because vertigo can sometimes make a child anxious, delivering the correct diagnosis and treatment at the early stage is important for preventing anxiety in affected children.
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http://dx.doi.org/10.3950/jibiinkoka.118.860DOI Listing
July 2015

Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats.

Neuropharmacology 2015 Dec 17;99:51-66. Epub 2015 Jul 17.

Discovery Research Laboratories I, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address:

Accumulating evidence has shown the pathophysiological significance of the translocator protein 18 kDa (TSPO) in the central nervous system. In this study, we evaluated the beneficial effects of ONO-2952, a novel TSPO antagonist in rat stress models. ONO-2952 potently bound both rat and human TSPO (Ki=0.330-9.30 nmol/L) with high selectivity over other receptors, transporters, ion channels and enzymes. ONO-2952 inhibited both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress. The inhibitory effect of ONO-2952 on stress-induced noradrenaline release was attenuated by co-treatment with the TSPO agonist CB34 in a dose-dependent manner. ONO-2952, at 0.3 mg/kg or higher, dose-dependently suppressed restraint stress-induced defecation in rats with brain TSPO occupancy of more than 50%. In addition, ONO-2952, at 1 mg/kg or higher, suppressed conditioned fear stress-induced freezing behavior in rats with an efficacy equivalent to that of diazepam, given orally at 3 mg/kg. Results of the passive avoidance learning test revealed that ONO-2952, unlike diazepam, did not affect learning and memory even at doses 10 times higher than its effective doses in the stress models. The present findings indicate that ONO-2952 is a promising candidate for the treatment of stress-related disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2015.07.011DOI Listing
December 2015

High prevalence of CDH23 mutations in patients with congenital high-frequency sporadic or recessively inherited hearing loss.

Orphanet J Rare Dis 2015 May 13;10:60. Epub 2015 May 13.

Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan.

Background: Mutations in CDH23 are responsible for Usher syndrome 1D and recessive non-syndromic hearing loss. In this study, we revealed the prevalence of CDH23 mutations among patients with specific clinical characteristics.

Methods: After excluding patients with GJB2 mutations and mitochondrial m.1555A > G and m.3243A > G mutations, subjects for CDH23 mutation analysis were selected according to the following criteria: 1) Sporadic or recessively inherited hearing loss 2) bilateral non-syndromic congenital hearing loss, 3) no cochlear malformation, 4) a poorer hearing level at high frequencies than at low frequencies, and 5) severe or profound hearing loss at higher frequencies.

Results: Seventy-two subjects were selected from 621 consecutive probands who did not have environmental causes for their hearing loss. After direct sequencing, 13 of the 72 probands (18.1%) had homozygous or compound heterozygous CDH23 mutations. In total, we identified 16 CDH23 mutations, including five novel mutations. The 16 mutations included 12 missense, two frameshift, and two splice-site mutations.

Conclusions: These results revealed that CDH23 mutations are highly prevalent in patients with congenital high-frequency sporadic or recessively inherited hearing loss and that the mutation spectrum was diverse, indicating that patients with these clinical features merit genetic analysis.
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http://dx.doi.org/10.1186/s13023-015-0276-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451718PMC
May 2015

Successful detection and genotyping of rubella virus from preserved umbilical cord of patients with congenital rubella syndrome.

Clin Infect Dis 2015 Feb 6;60(4):605-7. Epub 2014 Nov 6.

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

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http://dx.doi.org/10.1093/cid/ciu882DOI Listing
February 2015

Cricopharyngeal achalasia treated with myectomy and post-operative high-resolution manometry.

Int J Pediatr Otorhinolaryngol 2014 Jul 2;78(7):1182-5. Epub 2014 May 2.

Division of Surgery, Department of Surgical Specialties, National Center for Child Health and Development, Tokyo, Japan.

Cricopharyngeal achalasia is an uncommon cause of dysphagia in neonates or children. A nine-year-old female patient was referred to us with a long history of dysphagia, recurrent pulmonary infection and growth stunting. A gastrostomy was introduced to improve her nutritional condition and to minimize potential inflammation in the pharynx. Subsequently, cervical cricopharyngeal myectomy was conducted. The surgical intervention allowed prompt resolution of symptoms without complications. High-resolution manometry post myectomy demonstrated a significant reduction in upper esophageal pressure together with proper relaxation at deglutition. The patient was able to consume solid food and liquid normally, and remained asymptomatic without medications six months after the surgery.
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http://dx.doi.org/10.1016/j.ijporl.2014.04.036DOI Listing
July 2014

CT and endoscopic evaluation of larynx and trachea in mucopolysaccharidoses.

Mol Genet Metab 2014 Jun 4;112(2):154-9. Epub 2014 Apr 4.

Center for Lysosomal storage diseases, National Center for Child Health and Development, Japan.

Background: Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by lysosomal enzyme deficiencies that result in systemic accumulation of glycosaminoglycans (GAGs). Accumulation of GAGs in the upper airway can lead to respiratory failure. The aim of this study was to investigate changes of the airway by flexible endoscopy and CT.

Methods: Thirty-five patients aging from 2 to 16 years (mean: 9.2±4.4 years) participated in this study. The majority had MPS I (n=5) or MPS II (n=25). The shape of the trachea and the cross-sectional trachea surface area (TSA) was determined at the Th1 and Th2 levels. Airway obstruction was evaluated from endoscopic findings and classified into 3 grades (Grades 0, 1, and 2). Forty-five patients in the control group who underwent tracheal CT for other conditions were retrospectively selected from the database.

Results: Tracheal morphology was abnormal in 50-60%, which showed a transversely collapsing narrow trachea. Tracheal deformity was severe in MPS II and MPS IV. The mean TSA of the MPS patients was 55.5±29.0 mm(2) at Th1 and 61.4±29.0 mm(2) at Th2, while that of the control group was 90.1±41.9 mm(2) and 87.9±39.3 mm(2), respectively. Respiratory distress was noted in 15 of the 35 patients, among whom 7 patients showed tracheal deformity and 7 patients had laryngeal redundancy. Three patients had no abnormalities of the larynx or trachea, so other factors such as pharyngeal stenosis or lower airway stenosis might have contributed to their respiratory distress.

Conclusion: CT and flexible endoscopy allow quantitative and morphological evaluation of airway narrowing, which is beneficial for airway management in MPS children.
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http://dx.doi.org/10.1016/j.ymgme.2014.03.013DOI Listing
June 2014

Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study.

Orphanet J Rare Dis 2013 Oct 28;8:172. Epub 2013 Oct 28.

Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan.

Background: Genetic tests for hereditary hearing loss inform clinical management of patients and can provide the first step in the development of therapeutics. However, comprehensive genetic tests for deafness genes by Sanger sequencing is extremely expensive and time-consuming. Next-generation sequencing (NGS) technology is advantageous for genetic diagnosis of heterogeneous diseases that involve numerous causative genes.

Methods: Genomic DNA samples from 58 subjects with hearing loss from 15 unrelated Japanese families were subjected to NGS to identify the genetic causes of hearing loss. Subjects did not have pathogenic GJB2 mutations (the gene most often associated with inherited hearing loss), mitochondrial m.1555A>G or 3243A>G mutations, enlarged vestibular aqueduct, or auditory neuropathy. Clinical features of subjects were obtained from medical records. Genomic DNA was subjected to a custom-designed SureSelect Target Enrichment System to capture coding exons and proximal flanking intronic sequences of 84 genes responsible for nonsyndromic or syndromic hearing loss, and DNA was sequenced by Illumina GAIIx (paired-end read). The sequences were mapped and quality-checked using the programs BWA, Novoalign, Picard, and GATK, and analyzed by Avadis NGS.

Results: Candidate genes were identified in 7 of the 15 families. These genes were ACTG1, DFNA5, POU4F3, SLC26A5, SIX1, MYO7A, CDH23, PCDH15, and USH2A, suggesting that a variety of genes underlie early-childhood hearing loss in Japanese patients. Mutations in Usher syndrome-related genes were detected in three families, including one double heterozygous mutation of CDH23 and PCDH15.

Conclusion: Targeted NGS analysis revealed a diverse spectrum of rare deafness genes in Japanese subjects and underscores implications for efficient genetic testing.
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http://dx.doi.org/10.1186/1750-1172-8-172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231469PMC
October 2013

Subgroups of enlarged vestibular aqueduct in relation to SLC26A4 mutations and hearing loss.

Laryngoscope 2014 Apr 17;124(4):E134-40. Epub 2013 Dec 17.

Department of Otolaryngology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; Department of Otorhinolaryngology, Inagi Municipal Hospital, Tokyo, Japan; Department of Otolaryngology, Keio University Hospital, Tokyo, Japan.

Objectives/hypothesis: To investigate possible association of hearing loss and SLC26A4 mutations with the subgroups of enlarged vestibular aqueduct (EVA) morphology in Japanese subjects with hearing loss.

Study Design: Retrospective multicenter study.

Methods: Forty-seven subjects who had vestibular aqueduct with midpoint diameter >1 mm by computed tomography of the temporal bone were enrolled at multiple sites across Japan, and DNA samples and clinical data were collected. EVA morphology was classified into four subgroups by the pattern of enlargement: aperture, aperture and midpoint, midpoint, and borderline enlargement. Venous blood DNA samples were subjected to polymerase chain reaction-based direct sequencing of all exons and exon-intron boundaries of the SLC26A4.

Results: Four novel SLC26A4 mutations were identified in the present study. SLC26A4 mutations were detected in almost all subjects with aperture, aperture and midpoint, and midpoint enlargement. In contrast, 71% of subjects with borderline enlargement had no SLC26A4 mutation. No significant difference was found in the distribution of truncating and nontruncating SLC26A4 mutations between the EVA subgroups. In addition, no significant correlation was observed between the EVA subgroups and hearing levels, incidence of hearing fluctuation, or progression of hearing loss.

Conclusions: Subgroups of EVA morphology were significantly correlated with the presence or absence of SLC26A4 mutation. In a subgroup analysis of subjects with SLC26A4 mutations, however, differences in the EVA subgroups were not correlated with SLC26A4 genotypes or characteristics of hearing loss.

Level Of Evidence: NA.
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http://dx.doi.org/10.1002/lary.24368DOI Listing
April 2014
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