The clinical and genomic landscape of patients with DDX41 variants identified during diagnostic sequencing

Observation of a somatic DDX41 variant with a germline DDX41 variant can be integrated into existing ACMG frameworks to improve curation. Diverse types of genomic lesions can be responsible for pathogenic variants in DDX41, including synonymous variants and exon level deletions. Deleterious germline variants in DDX41 are a common cause of genetic predisposition to hematological malignancies, particularly myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Targeted next generation sequencing (NGS) was performed on large cohort of sequential patients with myeloid malignancy covering DDX41 as well as 30 other genes frequently mutated in myeloid malignancy. Whole genome transcriptome sequencing data was analyzed on a separate cohort of patients with a range of hematological malignancies to investigate the spectrum of cancer predisposition. 5737 patients with myeloid malignancies were studied with 152 different DDX41 variants detected. Multiple novel variants were detected, including synonymous variants affecting splicing as demonstrated by RNA-sequencing. The presence of a somatic DDX41 variant was highly associated with DDX41 germline variants in MDS and AML patients and we developed a statistical approach to incorporate the co-occurrence of a somatic DDX41 variant into germline variant classification at a “very strong” level (ACMG). Using this approach, the MDS cohort contained 3.8% (108/2865) patients with germline likely pathogenic/pathogenic (LP/P) variants and the AML cohort 4.9% (106/2157). DDX41 LP/P variants were markedly enriched in patients with AML and MDS compared to patients with myeloproliferative neoplasms (MPN), B-cell neoplasm and T- or B-cell acute lymphoblastic leukemia. In summary we have developed a framework to enhance DDX41 variant curation as well as highlighted the importance of assessment of all types of genomic variants (including synonymous and multi-exon deletions) in order to fully detect the landscape of possible clinically relevant DDX41 variants.