Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-12-28 Print Date: 2022-12-01 DOI:10.1101/mcs.a006242
Hayley M Reynolds, Ting Wen, Andrew Farrell, Rong Mao, Barry Moore, Steven E Boyden, Pinar Bayrak-Toydemir, Thomas J Nicholas, Shawn Rynearson, Carson Holt, Christine Miller, Katherine Noble, Dawn Bentley, Rachel Palmquist, Betsy Ostrander, Stephanie Manberg, Joshua L Bonkowsky, Brian J Shayota, Sabrina Malone Jenkins
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Abstract

Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al., Lancet Neurol 14: 420 [2015]; Finsterer, Orphanet J Rare Dis 14: 57 [2019]; Prior and Ghosh, J Child Neurol 36: 610 [2021]). The SNAP25-related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novo SNAP25 c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reported SNAP25 variant phenotype, and paves a foundation for personalized management for CMS18.

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快速基因组测序确定了新生儿先天性肌无力综合征的一个新的SNAP25变体。
先天性肌无力综合征(CMS)是一组 32 种疾病,涉及神经肌肉接头处的遗传功能障碍,导致骨骼肌无力,并在体力活动时加重。精确诊断和分子亚型鉴定对治疗至关重要,因为针对一种亚型的药物治疗可能会加重另一种亚型的病情(Engel 等,Lancet Neurol 14: 420 [2015];Finsterer,Orphanet J Rare Dis 14: 57 [2019];Prior 和 Ghosh,J Child Neurol 36: 610 [2021])。与 SNAP25 相关的 CMS 亚型(先天性肌无力综合征 18,CMS18;MIM #616330)是一种罕见疾病,以肌肉易疲劳、精神运动发育迟缓和共济失调为特征。在本文中,我们对一名重症新生儿进行了快速全基因组测序(rWGS),结果发现了一个未报告的致病性新生 SNAP25 c.529C > T; p.Gln177Ter 变异。在本报告中,我们介绍了一个具有复杂新生儿后果的 CMS18 新病例。这一发现为了解 CMS18 的表型严重程度提供了独特的见解,扩展了已报道的 SNAP25 变异表型,并为 CMS18 的个性化管理奠定了基础。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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