KMT2A-D pathogenicity, prevalence, and variation according to a population database.
Cancer Med
; 12(6): 7234-7245, 2023 03.
Article
em En
| MEDLINE
| ID: mdl-36479909
ABSTRACT
INTRODUCTION:
The KMT2 family of genes is essential epigenetic regulators promoting gene expression. The gene family contains three subgroups, each with two paralogues KMT2A and KMT2B; KMT2C and KMT2D; KMT2F and KMT2G. KMT2A-D are among the most frequent somatically altered genes in several different cancer types. Somatic KMT2A rearrangements are well-characterized in infant leukemia (IL), and growing evidence supports the role of additional family members (KMT2B, KMT2C, and KMT2D) in leukemogenesis. Enrichment of rare heterozygous frameshift variants in KMT2A and C has been reported in acute myeloid leukemia (AML), IL, and solid tumors. Currently, the non-synonymous variation, prevalence, and penetrance of these four genes are unknown.METHODS:
This study determined the prevalence of pathogenic/likely pathogenic (P/LP) germline KMT2A-D variants in a cancer-free adult population from the Genome Aggregation Database (gnomAD). Two methods of variant interpretation were utilized a manual genomic variant interpretation and an automated ACMG pipeline.RESULTS:
The ACMG pipeline identified considerably fewer P/LP variants (n = 89) compared to the manual method (n = 660) in all 4 genes. Consequently, the total P/LP prevalence and allele frequency (AF) were higher in the manual method (1112, AF = 4.46E-03) than in ACMG (1832, AF = 6.01E-04). Multiple ancestry-exclusive P/LP variants were identified along with an increased frequency in males compared to females. Many of these variants identified in this population database are also associated with severe juvenile conditions.CONCLUSION:
These data demonstrate that putatively functional germline variation in these developmentally important genes is more common than previously appreciated and identification in cancer-free adults may indicate incomplete penetrance for many of these variants. Future research should examine a genetic predisposing role in IL and other pediatric cancers.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prevalence_studies
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Risk_factors_studies
Limite:
Adult
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Child
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Female
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Humans
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Infant
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Male
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article