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

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

doi:10.1016/j.gim.2024.101227

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

Genet Med. 2024 Jul 30:101227. doi: 10.1016/j.gim.2024.101227. Online ahead of print.

Authors

Shuxiang Goh¹, Lavvina Thiyagarajan², Tracy Dudding-Byth³, Pinese Mark⁴, Edwin P Kirk⁵

Affiliations

¹ School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia; New South Wales Health, NSW, Australia. Electronic address: shuxiang.goh@health.nsw.gov.au.
² School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia; New South Wales Health, NSW, Australia; The Children's Hospital at Westmead, Sydney, NSW, Australia.
³ Hunter Genetics, Newcastle, NSW, Australia.
⁴ School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia; Children's Cancer Institute, Sydney, NSW, Australia.
⁵ School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia; New South Wales Health, NSW, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; NSW Health Pathology Randwick Genomics Laboratory, Sydney, NSW, Australia.

PMID: 39092588
DOI: 10.1016/j.gim.2024.101227

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, so 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 nine affected cohorts pooled and compared against the gnomAD v4.0 CNV control cohort of 269,885 individuals. Several CNVs previously associated with non-statistically 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 analysing penetrance and pathogenicity is provided for each of the 83 recurrent CNVs.

Keywords: deletion; duplication; intellectual disability; neurosusceptibility; prenatal.

Publication types

Review