Haematological malignancies cancer susceptibility

Gene: KDM1A

I don't know

Comment on list classification: Significant enrichment of KDM1A germline P/LP variants in MM patients has been identified and independently replicated. KDM1A has since been cited and acknowledged as a germline MM predisposition gene in the scientific literature. This may warrant inclusion on this panel to allow clinical surveillance of high-risk families, and therefore tagging for promotion to Green, subject to GMS expert review.

Created: 27 Oct 2025, 11:35 a.m. | Last Modified: 27 Oct 2025, 11:35 a.m.

Panel Version: 4.30

PMID: 29559475 (2018) identified KDM1A as a predisposition gene for multiple myeloma (MM) based on WES studies of familial and early-onset MM kindreds with variants in this gene. One family had three individuals affected by MM, one with acute myelogenous leukemia and monoclonal gammopathy of unknown significance (MGUS), and one unaffected at age 48 who all harboured a truncating KDM1A variant (c.805_806delAG [p.Arg269Aspfs*7]). Another truncating KDM1A variant (c.707delA [p.Gln236Hisfs*3]) was found in an individual with early-onset MM (age 59), with no family history of MM/MGUS. Using CADD ≥15 threshold two further predicted rare deleterious KDM1A missense variants (c.1424T>C [p.Leu475Pro] and c.2003G>C [p.Arg692Pro]) were identified in patients with first degree relatives also affected with MM/MGUS.

Mutation burden analysis indicated enrichment of germline KDM1A variants in MM patients unselected for family history compared to controls, with a prevalence of ~1.23% in MM patients and conferring ~9-fold increased risk of developing MM.

A more recent study (PMID: 39845416) replicated significant enrichment of germline P/LP variants in KDM1A (FDR = 0.045) in the familial MM cohort compared to controls. Truncating variants were associated with KDM1A expression in the bottom 25th percentile, which is consistent with the hypothesis of KDM1A having a role as a tumour suppressor gene in MM.

Created: 27 Oct 2025, 11:28 a.m. | Last Modified: 27 Oct 2025, 11:28 a.m.

Panel Version: 4.28

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Multiple myeloma

Publications

• 29559475
• 39845416

Green List (high evidence)

KDM1A is the first autosomal dominant MM germline predisposition gene, providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B cell differentiation (PMID: 29559475).
Sources: Expert list

Created: 8 Nov 2023, 9:30 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Multiple myeloma

Publications

• 29559475

Variants in this GENE are reported as part of current diagnostic practice