A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population

Determining the clinical significance of germline and somatic KMT2D missense variants (MVs) in Kabuki syndrome (KS) and cancers can be challenging. We analysed 1920 distinct KMT2D MVs that included 1535 germline MVs in controls (Control-MVs), 584 somatic MVs in cancers (Cancer-MVs) and 201 MV in ind...

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Bibliographic Details
Published in:Journal of human genetics 2019-02, Vol.64 (2), p.161-170
Main Authors: Faundes, Víctor, Malone, Geraldine, Newman, William G, Banka, Siddharth
Format: Article
Language:English
Subjects:
Amino acids
Cancer
Comparative analysis
Congenital defects
Consortia
Disease
Genes
Genomics
Mutation
Phenotypes
Protein folding
Protein interaction
Proteins
Splicing
Trends
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Summary:Determining the clinical significance of germline and somatic KMT2D missense variants (MVs) in Kabuki syndrome (KS) and cancers can be challenging. We analysed 1920 distinct KMT2D MVs that included 1535 germline MVs in controls (Control-MVs), 584 somatic MVs in cancers (Cancer-MVs) and 201 MV in individuals with KS (KS-MVs). The proportion of MVs likely to affect splicing was significantly higher for Cancer-MVs and KS-MVs than in Control-MVs (p = 0.000018). Our analysis identified significant clustering of Cancer-MVs and KS-MVs in the PHD#3 and #4, RING#4 and SET domains. Areas of enrichment restricted to just Cancer-MVs (FYR-C and between amino acids 3043-3248) or KS-MVs (coiled-coil#5, FYR-N and between amino acids 4995-5090) were also found. Cancer-MVs and KS-MVs tended to affect more conserved residues (lower BLOSUM scores, p 
ISSN:1434-5161
1435-232X
DOI:10.1038/s10038-018-0536-6