Epigenotype–genotype–phenotype correlations in SETD1A and SETD2 chromatin disorders
Human Molecular Genetics, vol. 32, pp. 3123–3134
Abstract
Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.
Authors 22
-
Affiliation as printed
Department of Medical Genetics, University of Cambridge , Cambridge CB2 0QQ , UK
-
Affiliation as printed
Department of Clinical Genetics, Great Ormond Street Hospital , London WC1N 3JH , UK
-
Affiliation as printed
Department of Clinical Genetics, Great Ormond Street Hospital , London WC1N 3JH , UK
-
Affiliation as printed
Department of Medical Genetics, University of Cambridge , Cambridge CB2 0QQ , UK
-
Affiliation as printed
Department of Medical Genetics, University of Cambridge , Cambridge CB2 0QQ , UK
Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus , Cambridge , UK
-
Affiliation as printed
Department of Medical Genetics, University of Cambridge , Cambridge CB2 0QQ , UK
Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus , Cambridge , UK
-
St Mary's Hospital · Manchester University NHS Foundation Trust
Affiliation as printed
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust , Saint Mary’s Hospital, Manchester , UK
Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Oxford Road, Manchester. UK
-
University Hospital Southampton NHS Foundation Trust
Affiliation as printed
Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust , Southampton , UK
-
Centre Hospitalier Universitaire Sainte-Justine · CHU Sainte-Justine Research Center · Université de Montréal
Affiliation as printed
CHU Sainte-Justine Research Centre , Montreal, Quebec , Canada
Department of Pediatrics, University of Montreal , Montreal, Quebec , Canada
Department of Pediatrics, University of Montreal, Meontreal, Qeuebec, Canada
-
Centre Hospitalier Universitaire Sainte-Justine · CHU Sainte-Justine Research Center
Affiliation as printed
CHU Sainte-Justine Research Centre , Montreal, Quebec , Canada
-
Affiliation as printed
Department of Neuropediatrics, University Hospital for Children and Adolescents , Leipzig , Germany
-
Affiliation as printed
Yorkshire Regional Genetics Service, Chapel Allerton Hospital , Leeds , UK
-
University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics , University of Groningen, , Groningen , The Netherlands
University Medical Center Groningen , University of Groningen, , Groningen , The Netherlands
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
-
Affiliation as printed
Patrick G Johnston Centre for Cancer Research and Cell Biology, Queens University Belfast , Belfast , UK
-
University Hospital Leipzig · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Leipzig University
Affiliation as printed
Center of Functional Genomics, Berlin Institute of Health at Charité, Universitätsmedizin Berlin , Berlin , Germany
Institute of Human Genetics, University of Leipzig Medical Center , Leipzig , Germany
-
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Hospital , Leiden , The Netherlands
-
Affiliation as printed
Department of Medical Genetics, University of Cambridge , Cambridge CB2 0QQ , UK
Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus , Cambridge , UK
-
Affiliation as printed
Department of Medical Genetics, University of Cambridge , Cambridge CB2 0QQ , UK
Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus , Cambridge , UK
-
University of Science and Technology of China
Affiliation as printed
MOE Key Laboratory for Cellular Dynamics , The School of Life Sciences, Division of Life Sciences and Medicine, , Hefei, Anhui 230026 , China
University of Science and Technology of China , The School of Life Sciences, Division of Life Sciences and Medicine, , Hefei, Anhui 230026 , China
MOE Key Laboratory for Cellular Dynamics, The School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China
-
Affiliation as printed
Department of Clinical Genetics, Great Ormond Street Hospital , London WC1N 3JH , UK
-
Cardiff and Vale University Health Board · University Hospital of Wales · National Health Service Wales
Affiliation as printed
All Wales Medical Genomics Service, NHS Wales Cardiff and Vale University Health Board and Institute of Medical Genetics, University Hospital of Wales , Heath Park, Cardiff , UK
-
Eamonn Richard Maher corresponding
Affiliation as printed
Department of Medical Genetics, University of Cambridge , Cambridge CB2 0QQ , UK
Cited by 18 stored of 18
18 results
No patents citing this paper on Lens.org (checked 2026-10-11).