基本情報
論文
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Genetics in medicine : official journal of the American College of Medical Genetics 101199-101199 2024年6月26日Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
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Journal of burn care & research : official publication of the American Burn Association 2024年2月14日Thermal airway injuries, usually accompanied by facial burns, require emergency management. We encountered a pediatric case of a late airway-scalding injury without any initial signs of scalding on the face or inside the oral cavity. A 16-month-old boy was accidentally exposed to boiling water from overhead and developed tachypnea and dyspnea at 8 h after the injury. When he visited our hospital at 12 h after the injury, there were no scalding-related findings on his face or inside his oral cavity; however, severe laryngeal edema was observed, which required emergency intubation. Thermal airway injuries can occur later, even if there is no evidence of facial or oral scalding immediately after the injury. Airway injuries should be considered when a patient has been exposed to hot water from overhead.
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Brain : a journal of neurology 2023年11月10日The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.
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Journal of inherited metabolic disease 2023年9月15日Biallelic variants in genes for seven out of eight subunits of the conserved oligomeric Golgi complex (COG) are known to cause recessive congenital disorders of glycosylation (CDG) with variable clinical manifestations. COG3 encodes a constituent subunit of the COG complex that has not been associated with disease traits in human. Herein, we report two COG3 homozygous missense variants in four individuals from two unrelated consanguineous families that co-segregated with COG3-CDG. Clinical phenotypes of affected individuals include global developmental delay, severe intellectual disability, microcephaly, epilepsy, facial dysmorphism, and variable neurological findings. Biochemical analysis of serum transferrin from one family showed the loss of a single sialic acid. Western blotting on patient-derived fibroblasts revealed reduced COG3 and COG4. Further experiments showed delayed retrograde vesicular recycling in patient cells. This report adds to the knowledge of the COG-CDG network by providing collective evidence for a COG3-CDG rare disease trait and implicating a likely pathology of the disorder as the perturbation of GA trafficking. This article is protected by copyright. All rights reserved.
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American journal of human genetics 110(8) 1229-1248 2023年8月3日Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.
MISC
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小児科臨床 76(6) 859-863 2023年12月Mendelson症候群は胃酸の誤嚥による化学性肺炎であり,誤嚥時および誤嚥後数時間以降の二相性の呼吸障害が特徴的である。意識障害,喉頭反射低下,フルストマックなどの状況がリスク因子である。熱性けいれん時の誤嚥により発症した重症のMendelson症候群を報告する。症例は1歳男児。昼食後に強直間代性けいれんが出現した。止痙後に嘔吐し,嘔吐後から低酸素血症を認め気管挿管された。第2病日に急激な肺高血圧から心停止に至り静脈脱血・動脈送血体外式膜型人工肺(venoarterial extracorporeal membrane oxygenation,以下VA ECMO)を導入した。その後,一酸化窒素吸入療法を含めた集学的治療を行い心機能および肺高血圧の所見は徐々に改善し第9病日にECMOを離脱,第38病日に明らかな神経学的後遺症はなく退院した。食後に発症したけいれんでは胃酸誤嚥のリスクが高く,経時的な呼吸循環動態の評価が重要である。(著者抄録)
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脳と発達 45(1) 53-57 2013年1月けいれんで発症し、精神症状や不随意運動を呈し、血液および髄液から抗NMDA受容体抗体が検出され、非腫瘍性抗NMDA受容体抗体脳炎と診断した8歳男児の症例を報告した。急性期のステロイドパルス療法やガンマグロブリン療法は効果がなかったが、月1回合計3クールのcyclophosphamide(CPA)のパルス療法(500mg/m2)後から髄液NMDA抗体価と平行して、症状が急速に改善し始め、発症6ヵ月後に明らかな神経学的合併症なく治癒した。CPA療法は、本症の小児における免疫抑制療法として、ステロイド療法やガンマグロブリン療法とともに考慮されるべき治療である。(著者抄録)
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こども医療センター医学誌 40(3) 185-190 2011年7月【目的】意思疎通の困難な小児神経疾患の急性呼吸不全に対するMechanically Assisted Coughing(MAC)の有効性と安全性を明らかにする。【対象】日常でMACを使用していない意思疎通困難な神経疾患児のうち、平成22年2月から5月に急性呼吸不全に対してMACを使用した当院に入院した症例を対象とした。【方法】診療録からの後方視的検討。MAC導入3日以内にPaCO2が20mmHg以上改善、SpO2≧95%となる酸素必要量の減少、P/F比100以上改善、5日以内に無気肺消失を認めた症例を有効、喀出量が増えたが有効と判定できない症例を境界、それ以外を無効として検討した。【結果】10例11回の入院でMACが施行された(0.2-20.4歳、中央値1.8歳)。autoモードで陽圧:陰圧:休止=1:1:2秒、圧±20-30cmH2Oで5呼吸を3-10サイクル、一日1-4セット施行した。有効5回、無効3回、境界3回であった。気胸や不整脈のような合併症は生じなかった。【結論】MACは意思疎通の困難な児の急性呼吸不全にも有効な例があり、安全に施行できることが分かった。(著者抄録)
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こども医療センター医学誌 38(3) 100-104 2009年7月5ヵ月女児。重症新生児仮死のため、1週間の脳低体温療法を施行した。明らかな神経学的異常所見なく、日齢15に退院し、里帰り分娩であったため、生後3ヵ月時にフォロー目的に紹介受診した。生後5ヵ月時、哺乳1時間後に全身性強直痙攣が出現し近医に救急搬送された。低血糖を認め、ブドウ糖加点滴静注を行い改善した。各種検査の結果、先天性高インスリン血症(CHI)と診断し、治療を継続した。入院後は、補液、経口哺乳に加え、diazoxideの内服を開始した。しかし、その後も、低血糖を認めることがあり、octreotide acetateの皮下注を追加し、血糖が安定した。手術に際して、びまん型と限局型を鑑別するために、[18F]-DOPA PETおよび遺伝子検査を行い、膵頭(鉤)部の限局型病変が強く疑われた。術後の血糖値は安定し、輸液および薬物療法は不要となった。また、膵液漏などの手術合併症を認めなかった。
共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2023年4月 - 2026年3月
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日本学術振興会 科学研究費助成事業 2022年4月 - 2025年3月
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日本学術振興会 科学研究費助成事業 2016年4月 - 2019年3月
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日本学術振興会 科学研究費助成事業 2013年4月 - 2015年3月