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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

ABSTRACT: Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.

SUBMITTER: Kaasinen E

PROVIDER: S-EPMC6424975 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

Kaasinen Eevi E Kuismin Outi O Rajamäki Kristiina K Ristolainen Heikki H Aavikko Mervi M Kondelin Johanna J Saarinen Silva S Berta Davide G DG Katainen Riku R Hirvonen Elina A M EAM Karhu Auli A Taira Aurora A Tanskanen Tomas T Alkodsi Amjad A Taipale Minna M Morgunova Ekaterina E Franssila Kaarle K Lehtonen Rainer R Mäkinen Markus M Aittomäki Kristiina K Palotie Aarno A Kurki Mitja I MI Pietiläinen Olli O Hilpert Morgane M Saarentaus Elmo E Niinimäki Jaakko J Junttila Juhani J Kaikkonen Kari K Vahteristo Pia P Skoda Radek C RC Seppänen Mikko R J MRJ Seppänen Mikko R J MRJ Eklund Kari K KK Taipale Jussi J Kilpivaara Outi O Aaltonen Lauri A LA

Nature communications 20190319 1

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional ...[more]

PMID: 30890702

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Project description:BackgroundDYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms.MethodsPhenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents.ResultsDYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype.ConclusionsResults confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background.

Dataset Information

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

Publications

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.

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