体细胞嵌合性疾病中的变异分析

Profiling variants in disorders of somatic mosaicism.

作者信息

Mojarad Bahareh A, Hernandez Patricia V, Evenson Michael J, Corliss Meagan M, Stein Sarah L, Theos Amy, Coughlin Carrie C, Sisk Bryan, Menezes Maithilee, Schroeder Molly C, Heusel Jonathan W, Neidich Julie A, Cao Yang

机构信息

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.

Section of Dermatology, Departments of Medicine and Pediatrics, University of Chicago, Chicago, IL.

出版信息

Genet Med Open. 2023 May 6;1(1):100815. doi: 10.1016/j.gimo.2023.100815. eCollection 2023.

DOI:10.1016/j.gimo.2023.100815

PMID:39669231

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11613552/

Abstract

PURPOSE

Variants in (encoding p110α; the catalytic subunit of PI3K) characterize some disorders of somatic mosaicism (DoSM) conditions with clinical features, including sporadic overgrowth and vascular malformations. Here, we profile variants in DoSM.

METHODS

We applied a next-generation, sequencing-based, laboratory-developed test, using an average coverage of approximately 2000× for up to 37 genes associated with DoSM, on a cohort of 1197 patients with DoSM referred for clinical genomics services between 2013 and 2022.

RESULTS

We identified clinically reportable variants in 747 (62.4%) individuals in this cohort. Notably, 371 clinically reportable variants in were identified in 368 patients, constituting approximately 49.2% of all patients with reportable findings. Variants in the C2 domain of p110α are enriched in DoSM (this cohort) compared with those of cancer (Catalogue of Somatic Mutations in Cancer [COSMIC] database), highlighting the role of the C2 domain in driving uncontrolled cell proliferation in DoSM. Furthermore, we report 17 novel variants in that are not previously reported in DoSM and describe clinical presentation correlation for 4 novel variants.

CONCLUSION

Our findings from the largest single-center cohort of patients with DoSM expand the spectrum of variants in and shed light on the less-studied role of the C2 domain in the pathogenesis of DoSM.

摘要

目的

PIK3CA（编码p110α；PI3K的催化亚基）中的变异可表征某些具有临床特征的体细胞镶嵌性疾病（DoSM），包括散发性过度生长和血管畸形。在此，我们对DoSM中的PIK3CA变异进行分析。

方法

我们应用了一种基于测序的实验室自主研发的新一代检测方法，对2013年至2022年间转诊至临床基因组学服务部门的1197例DoSM患者进行检测，平均覆盖约2000×，检测多达37个与DoSM相关的基因。

结果

我们在该队列中的747名（62.4%）个体中鉴定出可临床报告的变异。值得注意的是，在368例患者中鉴定出371个PIK3CA的可临床报告变异，约占所有有报告结果患者的49.2%。与癌症（癌症体细胞突变目录[COSMIC]数据库）相比，DoSM（本队列）中p110α的C2结构域中的变异更为丰富，这突出了C2结构域在驱动DoSM中不受控制的细胞增殖中的作用。此外，我们报告了17个PIK3CA中的新变异，这些变异在DoSM中以前未被报道，并描述了4个新变异与临床表现的相关性。