The utility of cerebrospinal fluid–derived cell-free DNA in molecular diagnostics for the PIK3CA-related megalencephaly-capillary malformation (MCAP) syndrome: a case report

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-04-01 DOI:10.1101/mcs.a006188
Wei-Liang Chen, E. Pao, James Owens, I. Glass, C. Pritchard, Brain H Shirts, C. Lockwood, G. Mirzaa
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引用次数: 8

Abstract

The megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth disorder caused by mosaic gain-of-function variants in PIK3CA. It is characterized by megalencephaly or hemimegalencephaly, vascular malformations, somatic overgrowth, among other features. Epilepsy is commonly associated with MCAP, and a subset of individuals have cortical malformations requiring resective epilepsy surgery. Like other mosaic disorders, establishing a molecular diagnosis is largely achieved by screening lesional tissues (such as brain or skin), with a low diagnostic yield from peripheral tissues (such as blood). Therefore, in individuals with MCAP in whom lesional tissues are scarce or unavailable or those ineligible for epilepsy surgery, establishing a molecular diagnosis can be challenging. Here we report on the utility of cerebrospinal fluid (CSF)-derived cfDNA for the molecular diagnosis of an individual with MCAP syndrome harboring a mosaic PIK3CA variant (c.3139C > T, p.His1047Tyr). The proband presented with asymmetric megalencephaly without significant dysgyria. He did not have refractory epilepsy and was therefore not a candidate for epilepsy surgery. However, he developed diffuse large B-cell lymphoma (DLBCL) in late childhood, with four CSF samples obtained via lumbar puncture for cancer staging during which one sample was collected for cfDNA extraction and sequencing. PIK3CA variant allele fractions in CSF cell-free DNA (cfDNA), skin fibroblasts, and peripheral blood were 3.08%, 37.31%, and 2.04%, respectively. This report illustrates the utility of CSF-derived cfDNA in MCAP syndrome. Minimally invasive–based molecular diagnostic approaches utilizing cfDNA not only facilitate accurate genetic diagnosis but also have important therapeutic implications for individuals with refractory epilepsy as repurposed PI3K-AKT-MTOR pathway-inhibitors become more widely available.
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脑脊液来源的无细胞DNA在pik3ca相关的巨脑-毛细血管畸形(MCAP)综合征分子诊断中的应用:一个病例报告
巨脑-毛细血管畸形(MCAP)综合征是一种由PIK3CA嵌合功能获得变异引起的过度生长障碍。它的特点是大脑畸形或半大脑畸形,血管畸形,体细胞过度生长,以及其他特征。癫痫通常与MCAP相关,并且一部分个体有皮质畸形,需要切除性癫痫手术。与其他花叶病一样,建立分子诊断主要是通过筛查病变组织(如脑或皮肤)来实现的,外周组织(如血液)的诊断率较低。因此,对于病变组织稀缺或无法获得或不适合癫痫手术的MCAP患者,建立分子诊断可能具有挑战性。在这里,我们报告了脑脊液(CSF)来源的cfDNA在MCAP综合征个体携带马赛克PIK3CA变异(c.3139C > T, p.His1047Tyr)的分子诊断中的应用。先证者表现为不对称巨脑畸形,无明显脑功能障碍。他没有难治性癫痫,因此不适合进行癫痫手术。然而,他在儿童晚期发展为弥漫性大b细胞淋巴瘤(DLBCL),通过腰椎穿刺获得4份脑脊液样本用于癌症分期,其中1份样本用于cfDNA提取和测序。PIK3CA变异等位基因在CSF无细胞DNA (cfDNA)、皮肤成纤维细胞和外周血中的比例分别为3.08%、37.31%和2.04%。本报告阐述了csf来源的cfDNA在MCAP综合征中的应用。基于cfDNA的微创分子诊断方法不仅有助于准确的遗传诊断,而且随着PI3K-AKT-MTOR通路抑制剂的应用越来越广泛,对难治性癫痫患者具有重要的治疗意义。
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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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