两个患有桥小脑发育不全2D型的兄弟姐妹的双等位SEPSECS变异强调了剪接破坏同义变异在疾病中的相关性。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-03-24 Print Date: 2022-02-01 DOI:10.1101/mcs.a006165
Swetha Ramadesikan, Scott Hickey, Emily De Los Reyes, Anup D Patel, Samuel J Franklin, Patrick Brennan, Erin Crist, Kristy Lee, Peter White, Kim L McBride, Daniel C Koboldt, Richard K Wilson
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引用次数: 0

摘要

通过选择性剪接发挥作用的非编码和同义编码变异体越来越被认为是一类重要的致病变异体。在这个报告中,我们描述了两个兄弟姐妹谁提出张力不足,深度发育迟缓,和癫痫发作。先证者5岁时的脑磁共振成像(MRI)显示弥漫性脑和小脑白质体积损失。两个兄弟姐妹后来都出现了呼吸机依赖型呼吸功能不全和脊柱侧凸,目前不能说话,也不能走动。包括寡核苷酸阵列和临床外显子组测序在内的广泛分子检测无法诊断。在机构审查委员会(IRB)批准的研究方案下,研究基因组测序显示,两名受影响的儿童都是SEPSECS基因变异的复合杂合。一种变异是启动密码子改变(c.1A > T),破坏了蛋白质翻译,这与大多数致病变异是功能丧失改变的观察结果一致。另一种变体是编码变化(c.846G > a),预测是同义的,但在迷你基因试验中已被证明会破坏mRNA剪接。SEPSECS基因编码O-phosphoseryl-tRNA(Sec)硒转移酶,该酶参与体内硒蛋白的生物合成和转运。SEPSECS变异可引起常染色体隐性桥小脑发育不全2D型(PCHT 2D;OMIM #613811),一种以进行性脑小脑萎缩、小头畸形和癫痫性脑病为特征的神经退行性疾病。该家族双等位基因致病变异的鉴定——其中一个是之前临床检测未发现的同义性变异——不仅结束了该家族的诊断历程,而且强调了标准基因检测方法可能无法识别的隐性致病变异的贡献。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease.

Noncoding and synonymous coding variants that exert their effects via alternative splicing are increasingly recognized as an important category of disease-causing variants. In this report, we describe two siblings who presented with hypotonia, profound developmental delays, and seizures. Brain magnetic resonance imaging (MRI) in the proband at 5 yr showed diffuse cerebral and cerebellar white matter volume loss. Both siblings later developed ventilator-dependent respiratory insufficiency and scoliosis and are currently nonverbal and nonambulatory. Extensive molecular testing including oligo array and clinical exome sequencing was nondiagnostic. Research genome sequencing under an institutional review board (IRB)-approved study protocol revealed that both affected children were compound-heterozygous for variants in the SEPSECS gene. One variant was an initiator codon change (c.1A > T) that disrupted protein translation, consistent with the observation that most disease-causing variants are loss-of-function changes. The other variant was a coding change (c.846G > A) that was predicted to be synonymous but had been demonstrated to disrupt mRNA splicing in a minigene assay. The SEPSECS gene encodes O-phosphoseryl-tRNA(Sec) selenium transferase, an enzyme that participates in the biosynthesis and transport of selenoproteins in the body. Variations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (PCHT 2D; OMIM #613811), a neurodegenerative condition characterized by progressive cerebrocerebellar atrophy, microcephaly, and epileptic encephalopathy. The identification of biallelic pathogenic variants in this family-one of which was a synonymous change not identified by prior clinical testing-not only ended the diagnostic odyssey for this family but also highlights the contribution of occult pathogenic variants that may not be recognized by standard genetic testing methodologies.

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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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