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

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.

Cancer-associated DNA Hypermethylation of Polycomb Targets Requires DNMT3A Dual Recognition of Histone H2AK119 Ubiquitination and the Nucleosome Acidic Patch

“…In particular, its PWWP domain recognizes histone H3K36 di-and tri-methylation (H3K36me2/3), which facilitates targeting to gene bodies and promoter-proximal intergenic regions of highly expressed genes (27)(28)(29)(30)(31). Missense mutations that disrupt the DNMT3A PWWP-H3K36me2/3 interaction have been reported in patients with Heyn-Sproul-Jackson syndrome or rare neuroendocrine tumors (32)(33)(34). Interestingly, cells harboring DNMT3A PWWP mutations showed increased DNMT3A1 localization and DNA hypermethylation at promoter CGIs of Polycomb target genes (32,(35)(36)(37).…”

Update on the genetics of paragangliomas

“…A second study confirmed the role of DNMT3A in the susceptibility to develop H&N PGL ( Table 1 ). The patient presented with multiple clinical features, a finding that suggested a heterogeneous phenotypic spectrum related to DNMT3A germline variants ( Mellid et al 2020 ).…”

The Study of Cancer Susceptibility Genes

“…DNA methylation patterns provide a paradigm for the epigenetic inheritance of cancer susceptibility, with emphasis on co-methylated networks [ 9 ]. Multiple paragangliomas and papillary thyroid carcinoma are likely connected to mutations in the DNMT3a gene, responsible for de novo methylation [ 10 ]…”

“…DNA methylation patterns provide a paradigm for the epigenetic inheritance of cancer susceptibility, with emphasis on co-methylated networks [9]. Multiple paragangliomas and papillary thyroid carcinoma are likely connected to mutations in the DNMT3a gene, responsible for de novo methylation [10] Changes in developmental programs do not necessarily involve DNA or RNA. The widespread Alzheimer's disease is connected to the accumulation of misfolded polymerized proteins, amyloid β (Aβ) and tau, in brains, and to neuronal degeneration, dementia, and death.…”