Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders

Sunwoo Lee, Lara Menzies, Eleanor Hay, Eguzkine Ochoa, France Docquier, Fay Rodger, Charu Deshpande, Nicola C. Foulds, Sébastien Jacquemont, Khadije Jizi, Henriette Kiep, Alison Kraus, Katharina Löhner, Patrick J. Morrison, Bernt Popp, Ruth Richardson, Arie van Haeringen, Ezequiel Martin, Ana Toribio, Fudong LiWendy D. Jones, Francis H. Sansbury, Eamonn R. Maher

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3123-3134
Number of pages12
JournalHuman Molecular Genetics
Issue number22
Early online date11 May 2023
Publication statusPublished - 15 Nov 2023

Bibliographical note

Copyright © The Author(s) 2023. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.


  • Humans
  • Chromatin/genetics
  • DNA Methylation/genetics
  • Mutation
  • Neurodevelopmental Disorders/genetics
  • Genetic Association Studies
  • Codon


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