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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Partial Duplications of Haploinsufficient Genes: A ...
Partial Duplications of Haploinsufficient Genes: Always a VUS?
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Pdf Summary
Copy number variation (CNV) is a significant factor in genetic disorders, with deletions of haploinsufficient (HI) genes being relatively easy to interpret. However, duplications of these genes are more complex. While most duplications are in direct tandem orientation with the original gene, duplications with one breakpoint in an HI gene can disrupt its function. Therefore, many partial duplications of haploinsufficient genes are classified as variants of uncertain significance (VUS). To better understand these CNVs, researchers analyzed and cataloged regions intersecting HI genes.<br /><br />Using a microarray database, the researchers analyzed germline duplications less than 5 Mb in size from patients tested between 2011 and 2022. They specifically looked for partial duplications involving 346 genes with strong evidence of haploinsufficiency. They identified over 600 partial gene duplications with one breakpoint in an HI gene. The most common genes involved in these duplications were ABCD1, TRIO, KMT2C, TRIP12, POGZ, MAGT1, SHOX, STS, ZMYND11, GRIN2A, MYT1L, CHEK2, NFIA, CHD2, and AUTS2.<br /><br />The researchers compared these CNVs to databases such as DGV, ClinVar, gnomAD, and DECIPHER. They found that many of the partial gene duplications involving HI genes were also present in population-based databases, indicating that they are likely benign variants without a functional impact on the gene. Although these duplications overlapped with clinically relevant HI genes, they do not appear to lead to loss-of-function.<br /><br />The study suggests that many partial duplications of HI genes are likely population variants rather than clinically significant. Further investigations into the inheritance and structure of these partial gene duplications will provide more evidence to support these findings.
Asset Subtitle
Presenting Author - Katie Rudd, PhD, FACMG; Co-Author - Jian M. Zhao, PhD; Co-Author - Zoe K. Lewis, MS, CGC; Co-Author - Bo Hong, MD, FACMG; Co-Author - Erica F. Andersen, PhD, FACMG;
Meta Tag
array CGH
Chromosomal Abnormalities
Chromosome Structure/Function
Cytogenetics
Databases
Disruption
Genomic Structure
Microarray
Co-Author
Jian M. Zhao, PhD
Co-Author
Zoe K. Lewis, MS, CGC
Co-Author
Bo Hong, MD, FACMG
Co-Author
Erica F. Andersen, PhD, FACMG
Presenting Author
Katie Rudd, PhD, FACMG
Keywords
copy number variation
genetic disorders
deletions
haploinsufficient genes
duplications
variants of uncertain significance
microarray database
partial duplications
breakpoint
gene duplications
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