Mellid, SaraColoma, JavierCalsina, BrunaMonteagudo, MaríaRoldán-Romero, Juan MSantos, MaríaLeandro-García, Luis JLanillos, JavierMartínez-Montes, Ángel MRodríguez-Antona, CristinaMontero-Conde, CristinaMartínez-López, JoaquínAyala, RosaMatias-Guiu, XavierRobledo Batanero, MercedesCascón, Alberto2025-01-132025-01-132020-11-09Cancers (Basel) . 2020 Nov 9;12(11):3304https://hdl.handle.net/20.500.12105/26011Over 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 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 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 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 variants in paraganglioma, the description of a new alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to germline variants.This work was supported by the Instituto de Salud Carlos III (ISCIII), through the "Accion Estrategica en Salud" (AES) (projects PI18/00454 and PI17/01796 to A.C. and M.R., repectively), cofounded by the European Regional Development Fund (ERDF).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/DNMT3Agermline variantpapillary thyroid carcinomaparagangliomaAttribution-NonCommercial-NoDerivatives 4.0 International3318239712113304Cancers (BASEL)open access