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Papers - MIYA Fuyuki

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Clinical usefulness of multigene screening with phenotype-driven bioinformatics analysis for the diagnosis of patients with monogenic diabetes or severe insulin resistance.

Hosoe J, Miya F, Kadowaki H, Fujiwara T, Suzuki K, Kato T, Waki H, Sasako T, Aizu K, Yamamura N, Sasaki F, Kurano M, Hara K, Tanaka M, Ishiura H, Tsuji S, Honda K, Yoshimura J, Morishita S, Matsuzawa F, Aikawa SI, Boroevich KA, Nangaku M, Okada Y, Tsunoda T, Shojima N, Yamauchi T, Kadowaki T

Diabetes research and clinical practice (Diabetes Research and Clinical Practice) 169 108461 2020.11

ISSN 0168-8227

Aims: Monogenic diabetes is clinically heterogeneous and differs from common forms of diabetes (type 1 and 2). We aimed to investigate the clinical usefulness of a comprehensive genetic testing system, comprised of targeted next-generation sequencing (NGS) with phenotype-driven bioinformatics analysis in patients with monogenic diabetes, which uses patient genotypic and phenotypic data to prioritize potentially causal variants. Methods: We performed targeted NGS of 383 genes associated with monogenic diabetes or common forms of diabetes in 13 Japanese patients with suspected (n = 10) or previously diagnosed (n = 3) monogenic diabetes or severe insulin resistance. We performed in silico structural analysis and phenotype-driven bioinformatics analysis of candidate variants from NGS data. Results: Among the patients suspected having monogenic diabetes or insulin resistance, we diagnosed 3 patients as subtypes of monogenic diabetes due to disease-associated variants of INSR, LMNA, and HNF1B. Additionally, in 3 other patients, we detected rare variants with potential phenotypic effects. Notably, we identified a novel missense variant in TBC1D4 and an MC4R variant, which together may cause a mixed phenotype of severe insulin resistance. Conclusions: This comprehensive approach could assist in the early diagnosis of patients with monogenic diabetes and facilitate the provision of tailored therapy.

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Serum anti-recoverin antibodies is found in elderly patients with retinitis pigmentosa and cancer.

Sato T, Nishiguchi KM, Fujita K, Miya F, Inoue T, Sasaki E, Asano T, Tsuda S, Shiga Y, Kunikata H, Nakazawa M, Nakazawa T

Acta ophthalmologica (Acta Ophthalmologica) 98 ( 6 ) e722 - e729 2020.09

ISSN 1755-375X

Purpose: To screen for anti-recoverin antibodies in elderly patients with retinitis pigmentosa (RP) with or without cancer and cross-sectionally characterize the seropositive patients clinically. Methods: Serum from 75 RP patients who had been tested for mutations in a panel of 83 RP genes and 73 normal controls, all aged 50–80 years, were screened for anti-recoverin antibodies by Western blot using recombinant recoverin, retinal lysate from a marmoset and commercial anti-recoverin antibodies as a control. Results: Three RP patients with typical pigmentary degeneration of the 75 (4.0%) were seropositive for anti-recoverin antibody. Pathogenic mutations were identified in two seropositive RP patients. All three patients had visual impairment since childhood and were diagnosed as RP by the age of 30. The severity of the retinopathy varied greatly among these three patients, ranging in visual acuity from light perception OU to 20/30 OU. Retinitis pigmentosa (RP) patients with a history of cancer were more likely to have anti-recoverin antibodies (3/14; 21.4%) than those without (0/61; 0%; p = 0.005, Fischer exact test). All 73 healthy controls with no history of cancer were also seronegative. Conclusion: Our results show that serum anti-recoverin antibodies can be detected in typical RP patients with identified pathogenic mutations and that a history of cancer may increase the risk of developing anti-recoverin antibodies.

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Quantification of multicellular colonization in tumor metastasis using exome-sequencing data.

Nishino J, Watanabe S, Miya F, Kamatani T, Sugawara T, Boroevich KA, Tsunoda T

International journal of cancer (International Journal of Cancer) 146 ( 9 ) 2488 - 2497 2020.05

ISSN 0020-7136

Metastasis is a major cause of cancer-related mortality, and it is essential to understand how metastasis occurs in order to overcome it. One relevant question is the origin of a metastatic tumor cell population. Although the hypothesis of a single-cell origin for metastasis from a primary tumor has long been prevalent, several recent studies using mouse models have supported a multicellular origin of metastasis. Human bulk whole-exome sequencing (WES) studies also have demonstrated a multiple “clonal” origin of metastasis, with different mutational compositions. Specifically, there has not yet been strong research to determine how many founder cells colonize a metastatic tumor. To address this question, under the metastatic model of “single bottleneck followed by rapid growth,” we developed a method to quantify the “founder cell population size” in a metastasis using paired WES data from primary and metachronous metastatic tumors. Simulation studies demonstrated the proposed method gives unbiased results with sufficient accuracy in the range of realistic settings. Applying the proposed method to real WES data from four colorectal cancer patients, all samples supported a multicellular origin of metastasis and the founder size was quantified, ranging from 3 to 17 cells. Such a wide-range of founder sizes estimated by the proposed method suggests that there are large variations in genetic similarity between primary and metastatic tumors in the same subjects, which may explain the observed (dis)similarity of drug responses between tumors.

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

Mutai H, Wasano K, Momozawa Y, Kamatani Y, Miya F, Masuda S, Morimoto N, Nara K, Takahashi S, Tsunoda T, Homma K, Kubo M, Matsunaga T

PLoS genetics (PLoS Genetics) 16 ( 4 ) e1008643 2020.04

ISSN 1553-7390

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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Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs.

Onodera K, Shimojo D, Ishihara Y, Yano M, Miya F, Banno H, Kuzumaki N, Ito T, Okada R, de Araújo Herculano B, Ohyama M, Yoshida M, Tsunoda T, Katsuno M, Doyu M, Sobue G, Okano H, Okada Y

Molecular brain (Molecular Brain) 13 ( 1 ) 18 2020.02

Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients' pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9 e438 ::Venus, and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.

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Single AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice.

Nishiguchi KM, Fujita K, Miya F, Katayama S, Nakazawa T

Nature communications (Nature Communications) 11 ( 1 ) 482 2020.01

Supplementing wildtype copies of functionally defective genes with adeno-associated virus (AAV) is a strategy being explored clinically for various retinal dystrophies. However, the low cargo limit of this vector allows its use in only a fraction of patients with mutations in relatively small pathogenic genes. To overcome this issue, we developed a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end-joining (MMEJ). In blind mice, the mutation replacement rescued approximately 10% of photoreceptors, resulting in an improvement in light sensitivity and an increase in visual acuity. These effects were comparable to restoration mediated by gene supplementation, which targets a greater number of photoreceptors. This strategy may be applied for the treatment of inherited disorders caused by mutations in larger genes, for which conventional gene supplementation therapy is not currently feasible.

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Integrative immunogenomic analysis of gastric cancer dictates novel immunological classification and the functional status of tumor-infiltrating cells.

Sato Y, Wada I, Odaira K, Hosoi A, Kobayashi Y, Nagaoka K, Karasaki T, Matsushita H, Yagi K, Yamashita H, Fujita M, Watanabe S, Kamatani T, Miya F, Mineno J, Nakagawa H, Tsunoda T, Takahashi S, Seto Y, Kakimi K

Clinical & translational immunology (Clinical and Translational Immunology) 9 ( 10 ) e1194 2020

Objectives: A better understanding of antitumor immunity will help predict the prognosis of gastric cancer patients and tailor the appropriate therapies in each patient. Therefore, we propose a novel immunological classification of gastric cancer. Methods: We performed whole-exome sequencing (WES), RNA-Seq and flow cytometry in 29 gastric cancer patients who received surgery. The TCGA data set of 323 gastric cancer patients and RNA-Seq data of 45 patients who received pembrolizumab (Kim et al. Nat Med 2018; 24: 1449–1458) were also analysed. Results: Immunogram analysis of cancer–immunity interaction of gastric cancer revealed immune signatures of four main types, designated Hot1, Hot2, Intermediate and Cold. Immunologically hot tumors displayed a dysfunctional T-cell signature, while cold tumors had an exclusion signature. Ex vivo tumor-infiltrating lymphocyte analysis documented T-cell dysfunction with the expression of checkpoint molecules and impaired cytokine production. The T-cell function was more profoundly damaged in Hot1 than Hot2 tumors. Patients in Hot2 subtypes had better survival in our cohort and TCGA cohort. Although these immunological subtypes overlapped to some degree with the molecular subtypes in the TCGA, intratumoral immune responses cannot be predicted solely based on histological or molecular subtyping of gastric cancer. Molecular and immunological classifications complement each other to predict the responses to anti-PD-1 therapy and have the potential to be a biomarker for the treatment of gastric cancer. Conclusion: The immunological classification of gastric cancer resulted in four subtypes. Hot tumors were further divided into two subtypes, between which the functional status of T cells was different.

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Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study

Nishiguchi KM and Miya F and Mori Y and Fujita K and Akiyama M and Kamatani T and Koyanagi Y and Kota S and Takigawa T and Ueno S and Tsugita M and Kunikata H and Cisarova K and Nishino J and Nakazawa T

2019.12

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Author Correction: A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate.

Kato K, Miya F, Hori I, Ieda D, Ohashi K, Negishi Y, Hattori A, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Saitoh S

Journal of human genetics (Journal of Human Genetics) 64 ( 7 ) 701 - 702 2019.07

ISSN 1434-5161

Since the publication of this article, it has been brought to our attention, that the identified mutation (NM_015277: c.2617 G > A; p.Glu873Lys) is identical with the mutation (NM_001144967: c.2677 G > A; p.Glu893Lys) reported by Broix et al (Nature Genetics 48, 1349–1358, 2016 https://doi.org/10.1038/ng.3676). Therefore the mutation is not novel but recurrent. Accordingly, the word “novel” should be deleted throughout the article including the title. Thus, the title should read “A missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria, and cleft palate”.

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A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy.

Nikopoulos K, Cisarova K, Quinodoz M, Koskiniemi-Kuendig H, Miyake N, Farinelli P, Rehman AU, Khan MI, Prunotto A, Akiyama M, Kamatani Y, Terao C, Miya F, Ikeda Y, Ueno S, Fuse N, Murakami A, Wada Y, Terasaki H, Sonoda KH, Ishibashi T, Kubo M, Cremers FPM, Kutalik Z, Matsumoto N, Nishiguchi KM, Nakazawa T, Rivolta C

Nature communications (Nature Communications) 10 ( 1 ) 2884 2019.06

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

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<i>MYCN</i> de novo gain-of-function mutation in a patient with a novel megalencephaly syndrome.

Kato K, Miya F, Hamada N, Negishi Y, Narumi-Kishimoto Y, Ozawa H, Ito H, Hori I, Hattori A, Okamoto N, Kato M, Tsunoda T, Kanemura Y, Kosaki K, Takahashi Y, Nagata KI, Saitoh S

Journal of medical genetics (Journal of Medical Genetics) 56 ( 6 ) 388 - 395 2019.06

ISSN 0022-2593

background in this study, we aimed to identify the gene abnormality responsible for pathogenicity in an individual with an undiagnosed neurodevelopmental disorder with megalencephaly, ventriculomegaly, hypoplastic corpus callosum, intellectual disability, polydactyly and neuroblastoma. We then explored the underlying molecular mechanism. Methods trio-based, whole-exome sequencing was performed to identify disease-causing gene mutation. Biochemical and cell biological analyses were carried out to elucidate the pathophysiological significance of the identified gene mutation. results We identified a heterozygous missense mutation (c.173c>t; p.thr58Met) in the MYCN gene, at the thr58 phosphorylation site essential for ubiquitination and subsequent MYcn degradation. the mutant MYcn (MYcn-t58M) was non-phosphorylatable at thr58 and subsequently accumulated in cells and appeared to induce ccnD1 and ccnD2 expression in neuronal progenitor and stem cells in vitro. Overexpression of Mycn mimicking the p.thr58Met mutation also promoted neuronal cell proliferation, and affected neuronal cell migration during corticogenesis in mouse embryos. Conclusions We identified a de novo c.173c>t mutation in MYCN which leads to stabilisation and accumulation of the MYcn protein, leading to prolonged ccnD1 and ccnD2 expression. this may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause Feingold syndrome, this is the first report of a germline gain-of-function mutation in MYCN identified in a patient with a novel megalencephaly syndrome similar to, but distinct from, ccnD2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. the data obtained here provide new insight into the critical role of MYcn in brain development, as well as the consequences of MYcn defects.

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難治性てんかんと退行を示したPOGZ変異症の1例

山形誠也, 服部文子, 宮冬樹, 久保田裕子, 遠藤剛, 根岸豊, 中村勇治, 角田達彦, 小崎健次郎, 齋藤伸治

脳と発達 ((一社)日本小児神経学会) 51 ( 1 ) 29 - 32 2019.01

ISSN 0029-0831

Pogo transposable element with zinc finger domain(POGZ)遺伝子は近年、本遺伝子の変異と自閉症スペクトラム障害および知的障害の関連性が指摘されている。これまでに40例の報告があり、言語発達遅滞、視力障害、小頭症、肥満傾向といった表現型が指摘されている。脳波異常は20%に報告されているが、てんかんとして治療を要した症例の報告はない。今回、これまでに報告のなかった難治性のてんかんと退行を有する症例にde novoのPOGZ遺伝子短縮型変異(c.2102del;p.Pro701Leufs*18)をヘテロ接合性に同定した。POGZ変異が原因となる表現型は自閉症スペクトラム障害に止まらず、多彩な神経症状を示し、進行性のてんかん症候群の原因となる可能性が示唆された。(著者抄録)

Refractory epilepsy and regression in a patient with a de novo heterozygous POGZ mutation

Yamagata S., Hattori A., Miya F., Kubota Y., Endo T., Negishi Y., Nakamura Y., Tsunoda T., Kosaki K., Saitoh S.

No To Hattatsu (No To Hattatsu) 51 ( 1 ) 29 - 32 2019

ISSN 00290831

Mutations in the pogo transposable element with zinc finger domain（POGZ）gene are associated with autism spectrum disorder （ASD）and intellectual disability. A total of 40 cases have been reported, and their clinical features include severe phenotypes such as severe speech and language delay, vision problems, microcephaly, and a predisposition towards obesity. Although 20% of these cases showed EEG abnormalities, epilepsy has not been reported. We present the case of a patient with refractory epilepsy and regression in which whole exome sequencing identified a de novo heterozygous POGZ mutation（c.2102del;p.Pro701Leufs ＊ 18）. He was diagnosed with autism spectrum disorder at 6 years of age. From 7 years and 8 months of age, he experienced epileptic seizures that involved falling backwards, head nodding and ocular deviation. An EEG showed a spike-and-slow-wave at F3 and F4. He was diagnosed with frontal lobe epilepsy, and treated with various anti-epileptic drugs （e.g. CZP, VPA, CLB, PHT, LTG, PB, CBZ and LEV）, which eventually reduced his epileptic seizures from over 10 to 2-3 times per day. Moreover, this patient had repetitive aspiration pneumonia from 14 years of age, necessitating a tracheotomy and laryngo-tracheal separation. Phenotypes associated with a POGZ mutation might, therefore, have a wider spectrum than previously recognized, and include not only ASD, but various neurological problems such as progressive epilepsy syndrome.

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Gene expression dataset for whole cochlea of Macaca fascicularis.

Mutai H, Miya F, Shibata H, Yasutomi Y, Tsunoda T, Matsunaga T

Scientific reports (Scientific Reports) 8 ( 1 ) 15554 2018.10

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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Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration.

Akiyama M, Takahashi A, Momozawa Y, Arakawa S, Miya F, Tsunoda T, Ashikawa K, Oshima Y, Yasuda M, Yoshida S, Enaida H, Tan X, Yanagi Y, Yasukawa T, Ogura Y, Nagai Y, Takahashi K, Fujisawa K, Inoue M, Arakawa A, Tanaka K, Yuzawa M, Kadonosono K, Sonoda KH, Ishibashi T, Kubo M

Journal of human genetics (Journal of Human Genetics) 63 ( 10 ) 1083 - 1091 2018.10

ISSN 1434-5161

To identify factors associated with ranibizumab responses in patients with exudative age-related macular degeneration (AMD), we performed a genome-wide association study (GWAS) and a replication study using a total of 919 exudative AMD patients treated with intravitreal ranibizumab in a Japanese population. In the combined analysis of GWAS and the replication study, no loci reached genome-wide significant level; however, we found four variants showed suggestive level of associations with visual loss at month three (rs17822656, rs76150532, rs17296444, and rs75165563: Pcombined < 1.0 × 10−5). Of the candidate genes within these loci, three were relevant to VEGF-related pathway (KCNMA1, SOCS2, and OTX2). The proportions of patients who worsened visual acuity were 13.7%, 38.8%, 58.0%, and 80.0% in patients with 0, 1, 2, and 3 or more identified risk variants, respectively. Changes in visual acuity decreased linearly as the number of risk variants increased (P = 1.67 × 10–12). The area under the curve using age, baseline visual acuity, and history of previous treatment was 0.607, and improved significantly to 0.713 in combination with identified variants (P < 0.0001). Although further study is needed to confirm their associations, our results offer candidate variants influencing response to ranibizumab therapy.

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A novel homozygous missense mutation in the SH3-binding motif of STAMBP causing microcephaly-capillary malformation syndrome.

Hori I, Miya F, Negishi Y, Hattori A, Ando N, Boroevich KA, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Saitoh S

Journal of human genetics (Journal of Human Genetics) 63 ( 9 ) 957 - 963 2018.09

ISSN 1434-5161

Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability. STAMBP interacts with the SH3 domain of STAM and transduces downstream signals from the Jaks-STAM complex. The substitution of Ser236Phe found in the case patient was located in the SH3-binding motif, and we propose the mutation may block STAM binding and subsequently induce STAMBP degradation. Contrary to previously reported STAMBP mutations, the Ser236Phe mutation did not lead to constitutive activation of the PI3K-AKT-mTOR pathway in patient-derived LCLs, as indicated by the expression of phosphorylated S6 ribosomal protein, suggesting that it is not the major pathomechanism underlying the disorder in this patient.

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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.

Suzuki N, Mutai H, Miya F, Tsunoda T, Terashima H, Morimoto N, Matsunaga T

BMC pediatrics (BMC Pediatrics) 18 ( 1 ) 171 2018.05

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

Shigemizu D, Miya F, Akiyama S, Okuda S, Boroevich KA, Fujimoto A, Nakagawa H, Ozaki K, Niida S, Kanemura Y, Okamoto N, Saitoh S, Kato M, Yamasaki M, Matsunaga T, Mutai H, Kosaki K, Tsunoda T

Scientific reports (Scientific Reports) 8 ( 1 ) 5608 2018.04

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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Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome.

Tamai K, Tada K, Takeuchi A, Nakamura M, Marunaka H, Washio Y, Tanaka H, Miya F, Okamoto N, Kageyama M

American journal of medical genetics. Part A (American Journal of Medical Genetics, Part A) 176 ( 3 ) 682 - 686 2018.03

ISSN 1552-4825

Raine syndrome is a rare osteosclerotic bone dysplasia characterized by craniofacial anomalies and intracranial calcification. Most patients with Raine syndrome are of Arab ancestry and die during the neonatal period. We herein report a Japanese patient with non-lethal Raine syndrome who presented with characteristic cerebral hyperechogenicity and a hypoplastic nose by fetal ultrasonography. She was admitted to the NICU due to pyriform aperture stenosis. Craniofacial abnormalities, intracranial calcification, osteosclerosis, chondrodysplasia punctata, and a mutation of FAM20C was identified. She was subsequently discharged without surgical intervention and is now 2 years old with mild neurodevelopmental delays. Images of cerebral hyperechogenicity by fetal ultrasonography in a non-lethal case were described herein for the first time. This patient represents a rare occurrence of a child with Raine syndrome born to Japanese parents and confirms that this syndrome is not always lethal. Even if Raine syndrome is suspected in a fetus due to cerebral hyperechogenicity and a hypoplastic nose, cerebral hyperechogenicity without pulmonary hypoplasia does not always predict lethality or severe neurodevelopmental delays. The information provided herein will be useful for prenatal counseling.

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Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa.

Ikeda Y, Nishiguchi KM, Miya F, Shimozawa N, Funatsu J, Nakatake S, Fujiwara K, Tachibana T, Murakami Y, Hisatomi T, Yoshida S, Yasutomi Y, Tsunoda T, Nakazawa T, Ishibashi T, Sonoda KH

Investigative ophthalmology & visual science (Investigative Ophthalmology and Visual Science) 59 ( 2 ) 826 - 830 2018.02

ISSN 0146-0404

PURPOSE. To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. METHODS. First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. RESULTS. Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother’s older brother) and his mother was her younger half-sibling sister with a different father. CONCLUSIONS. The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.

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