通过全外显子组测序鉴定一名致死性短肋胸廓发育不良 III 型患者体内 DYNC2H1 的新型深度内切变异体的特征。

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.a006254
Muqsit Buchh, Patrick J Gillespie, Kayla Treat, Marco A Abreu, Tae-Hwi Linus Schwantes-An, Benjamin M Helm, Fang Fang, Xiaoling Xuei, Lili Mantcheva, Kristen R Suhrie, Brett H Graham, Erin Conboy, Francesco Vetrini
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引用次数: 0

摘要

短肋胸廓发育不良 III 型伴有或不伴有多指畸形(OMIM #613091)的病因是 DYNC2H1 的双叶致病变体,这是一种骨骼纤毛症,其特征是胸廓因短肋骨而发育不良。在本报告中,我们回顾了印第安纳大学健康中心(Indiana University Health,IUH)新生儿重症监护室(NICU)收治的一名患者的病例,该患者因胸廓狭小导致限制性肺部疾病而出现呼吸窘迫,随后被送入新生儿重症监护室接受呼吸支持治疗。其他表型特征包括轴后多指畸形、近端长骨短小和生殖器畸形。外显子组测序(ES)发现,DYNC2H1基因中存在一个可能由母体遗传的致病变异体c.10322C > T p.(Leu3448Pro)。然而,在父系等位基因中没有发现变异。检测 DYNC2H1 基因缺失或重复的微阵列分析结果正常。因此,没有足够的证据确定分子诊断。为了进一步探索数据并进行更多检查,患者随后被纳入印第安纳大学医学院(Indiana University School of Medicine,IUSM)的未确诊罕见病诊所(Undiagnosed Rare Disease Clinic,URDC)。URDC的研究人员对ES原始数据进行了重新分析,结果发现了一个父系遗传的DYNC2H1深度内切变异c.10606-14A > G,预测该变异会产生一个强隐性接受剪接位点。此外,成纤维细胞的 RNA 测序表明,部分内含子保留会导致过早的终止密码子和无义介导的 mRNA 衰减(NMD)。液滴数字 RT-PCR(RT-ddPCR)显示,DYNCH2H1 mRNA 水平急剧下降了 74%。因此,该内含子变异随后被重新归类为可能致病的变异,从而为该患者做出了明确的临床和基因诊断。对 ES 和成纤维细胞 mRNA 实验的重新分析证实了剪接变体的致病性,补充了原始 ES 或 CMA 报告中未披露的关键信息。新生儿重症监护室(NICU)和 URDC 的合作结束了这个家庭的诊断之旅;此外,其重要性还体现在有可能对母亲的本次妊娠进行产前诊断。
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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Characterization of a novel deep-intronic variant in DYNC2H1 identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III.

Biallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.

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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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