Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma

SIMPLE SUMMARY: The use of next generation technologies has helped to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. Nonetheless, the sequencing of all protein-coding genes of an individual may lead to doubtful assignments of causality for non-pathological variants, so it is mandatory to perform comprehensive studies and screening of additional patients for new mutations. Here we describe a novel DNMT3A germline variant identified by whole-exome sequencing in a patient with multiple paragangliomas and papillary thyroid carcinoma. The increased methylation of DNMT3A target genes observed in the proband’s sample points towards a gain-of-function effect of the variant, contrasting with the inactivation caused by loss-of-function alterations commonly seen in other neoplasia and in patients with Tatton-Brown-Rahman syndrome. This finding stresses the diverse molecular outcomes and suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants. ABSTRACT: Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline DNMT3A variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of DNMT3A target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of DNMT3A variants in paraganglioma, the description of a new DNMT3A alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants.