2026-05-17T01:18:32Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/260112025-12-18T12:56:34Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991
Repisalud
author
Mellid, Sara
author
Coloma, Javier
author
Calsina, Bruna
author
Monteagudo, María
author
Roldán-Romero, Juan M
author
Santos, María
author
Leandro-García, Luis J
author
Lanillos, Javier
author
Martínez-Montes, Ángel M
author
Rodríguez-Antona, Cristina
author
Montero-Conde, Cristina
author
Martínez-López, Joaquín
author
Ayala, Rosa
author
Matias-Guiu, Xavier
author
Robledo Batanero, Mercedes
author
Cascón, Alberto
funder
Instituto de Salud Carlos III
funder
Unión Europea
2025-01-13T15:07:00Z
2025-01-13T15:07:00Z
2020-11-09
Cancers (Basel) . 2020 Nov 9;12(11):3304
Cancers (BASEL)
33182397
https://hdl.handle.net/20.500.12105/26011
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 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.
eng
DNMT3A
germline variant
papillary thyroid carcinoma
paraganglioma
Novel Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma.
research article
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