Pathogenic Copy Number and Sequence Variants in Children Born SGA With Short Stature Without Imprinting Disorders
Pathogenic Copy Number and Sequence Variants in Children Born SGA With Short Stature Without Imprinting Disorders
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DOI：
10.1210/clinem/dgac319
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发表时间：
2022-05-18
影响因子：
5.8
通讯作者：
Kagami, Masayo
中科院分区：
文献类型：
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作者：
Hara-Isono, Kaori;Nakamura, Akie;Kagami, Masayo
背景出生的小于胎龄儿身材矮小（SGA-SS）与（epi）遗传缺陷相关，包括印记疾病（ID），致病性拷贝数变异（PCNV）和与生长有关的致病性基因变异。然而，评价这三个因素的综合研究非常有限。目的阐明PCNV及其候选致病变异体在SGA-SS中的作用。设计包括甲基化分析、拷贝数分析和多基因测序的全面分子分析。方法我们收集了140例转介到我们进行SGA-SS基因检测的患者。其中，我们排除了42例符合Netchine-Harbison临床评分系统标准的Silver-Russell综合征患者和4例ID相关差异甲基化区域甲基化水平异常的患者。因此，我们进行了拷贝数分析和多基因测序的86例SGA-SS患者有足够的样本量。我们还评估了PCNV或候选致病性变体患者的临床表型。结果我们分别鉴定出8例（9.3%）和11例（12.8%）PCNV和候选致病变异体。根据美国医学遗传学学会标准和指南，5种变异被归类为致病性，其余6种变异被归类为意义不明的变异。12例患者进行了基因诊断。所有PCNV或候选致病性变异的患者并不完全符合每种特定遗传原因的特征性临床特征。结论阐明了PCNV和致病性变异体在无ID的SGA-SS中的作用。对于病因不明的SGA-SS患者，应考虑进行全面的分子分析，包括拷贝数分析和多基因测序。
Context Children born small-for-gestational-age with short stature (SGA-SS) is associated with (epi)genetic defects, including imprinting disorders (IDs), pathogenic copy number variants (PCNVs), and pathogenic variants of genes involved in growth. However, comprehensive studies evaluating these 3 factors are very limited. Objective To clarify the contribution of PCNVs and candidate pathogenic variants to SGA-SS. Design Comprehensive molecular analyses consisting of methylation analysis, copy number analysis, and multigene sequencing. Methods We enrolled 140 patients referred to us for genetic testing for SGA-SS. Among them, we excluded 42 patients meeting Netchine-Harbison clinical scoring system criteria for Silver-Russell syndrome and 4 patients with abnormal methylation levels of the IDs-related differentially methylated regions. Consequently, we conducted copy number analysis and multigene sequencing for 86 SGA-SS patients with sufficient sample volume. We also evaluated clinical phenotypes of patients with PCNVs or candidate pathogenic variants. Results We identified 8 (9.3%) and 11 (12.8%) patients with PCNVs and candidate pathogenic variants, respectively. According to the American College of Medical Genetics standards and guidelines, 5 variants were classified as pathogenic and the remaining 6 variants were classified as variants of unknown significance. Genetic diagnosis was made in 12 patients. All patients with PCNVs or candidate pathogenic variants did not correspond perfectly to characteristic clinical features of each specific genetic cause. Conclusion We clarified the contribution of PCNVs and pathogenic variants to SGA-SS without IDs. Comprehensive molecular analyses, including copy number analysis and multigene sequencing, should be considered for patients with unknown SGA-SS etiology.