A systematic review and pooled analysis of penetrance estimates of copy-number variants associated with neurodevelopment

IF 6.6 1区医学 Q1 GENETICS & HEREDITY Genetics in Medicine Pub Date : 2024-07-30 DOI:10.1016/j.gim.2024.101227

Shuxiang Goh , Lavvina Thiyagarajan , Tracy Dudding-Byth , Mark Pinese , Edwin P. Kirk

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Abstract

Purpose

Many copy-number variants (CNVs) are reported to cause a variety of neurodevelopmental disabilities including intellectual disability, developmental delay, autism, and other phenotypes with incomplete penetrance. Therefore, not all individuals with a pathogenic CNV are affected. Penetrance estimates vary between studies. A systematic review was conducted to clarify CNV penetrance for 83 recurrent CNVs.

Methods

A systematic review using PRISMA guidelines (PROSPERO #CRD42021253955) was conducted to identify penetrance estimates for CNVs associated with neurodevelopment. Pooled analysis was performed using forest plots. The Ottawa Risk of Bias Assessment facilitated evaluation.

Results

Fifteen studies were reviewed in detail with 9 affected cohorts pooled and compared with the gnomAD v4.0 CNV control cohort of 269,885 individuals. Several CNVs previously associated with nonstatistically significant penetrance estimates now exhibit statistically significant differences, contributing to emerging evidence for their pathogenicity (15q24 duplication [A-D breakpoints], 15q24.2q24.5 deletion and duplication [FBXO22], 17q11.2 duplication [NF1], 17q21.31 duplication [KANSL1] and 22q11.2 distal duplication). Additionally, evidence is presented for the benign nature of some CNVs (15q11.2 duplication [NIPA1] and 2q13 proximal duplication [NPHP1]).

Conclusion

This is a large-scale systematic review of CNVs associated with neurodevelopment. A synopsis analyzing penetrance and pathogenicity is provided for each of the 83 recurrent CNVs.

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对与神经发育相关的拷贝数变异的渗透率估算进行系统回顾和汇总分析。

目的：据报道，许多拷贝数变异（CNV）可导致各种神经发育障碍，包括智力障碍、发育迟缓、自闭症和其他表型，但这些变异具有不完全渗透性，因此并非所有具有致病性 CNV 的个体都会受到影响。不同研究对穿透性的估计也不尽相同。为了明确 83 个复发性 CNV 的 CNV 穿透性，我们进行了一项系统综述：采用 PRISMA 指南（PROSPERO #CRD42021253955）进行了一项系统性综述，以确定与神经发育相关的 CNV 的渗透率估计值。使用森林图进行了汇总分析。渥太华偏倚风险评估为评估提供了便利：详细审查了 15 项研究，汇集了 9 个受影响的队列，并与包含 269,885 人的 gnomAD v4.0 CNV 对照队列进行了比较。一些 CNV 之前与非统计意义上的穿透性估计值相关，现在则表现出统计意义上的显著差异，从而为其致病性提供了新的证据（15q24 重复 [A-D 断点]、15q24.2q24.5 缺失和重复 (FBXO22)、17q11.2 重复 (NF1)、17q21.31 重复 (KANSL1) 和 22q11.2 远端重复）。此外，还有证据表明一些 CNVs（15q11.2 重复（NIPA1）和 2q13 近端重复（NPHP1））是良性的：结论：这是一篇关于与神经发育相关的 CNV 的大规模系统性综述。结论：这是一篇与神经发育相关的 CNVs 的大规模系统综述，对 83 个复发性 CNVs 的穿透性和致病性进行了简要分析。

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来源期刊

Genetics in Medicine 医学-遗传学

CiteScore

15.20

自引率

6.80%

发文量

857

审稿时长

1.3 weeks

期刊介绍： Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health. GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.