Genotype–phenotype correlation at codon 1740 of SETD2

Rachel Rabin, Alireza Radmanesh, Ian A. Glass, William B. Dobyns, Kimberly A. Aldinger, Joseph T. Shieh, Shelby Romoser, Hannah Bombei, Leah Dowsett, Pamela Trapane, John A. Bernat, Janice Baker, Nancy J. Mendelsohn, Bernt Popp, Manuela Siekmeyer, Ina Sorge, Francis Hugh Sansbury, Patrick Watts, Nicola C. Foulds, Jennifer BurtonGeorge Hoganson, Jane A. Hurst, Lara Menzies, Deborah Osio, Larissa Kerecuk, Jan M. Cobben, Khadijé Jizi, Sebastien Jacquemont, Stacey A. Bélanger, Katharina Löhner, Hermine E. Veenstra-Knol, Henny H. Lemmink, Jennifer Keller-Ramey, Ingrid M. Wentzensen, Sumit Punj, Kirsty McWalter, Jerica Lenberg, Katarzyna A. Ellsworth, Kelly Radtke, Schahram Akbarian, John Pappas

Research output: Contribution to journalArticlepeer-review

Abstract

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.

Original languageEnglish (US)
Pages (from-to)2037-2048
Number of pages12
JournalAmerican Journal of Medical Genetics, Part A
Volume182
Issue number9
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
We would like to thank the patients and their families. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003], a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute [grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. This work was supported by the DFG grant PO2366/2-1 to B. P.

Funding Information:
Deutsche Forschungsgemeinschaft, Grant/Award Number: PO2366/2‐1; National Institute for Health Research; Republic of Ireland REC, Grant/Award Number: GEN/284/12; Cambridge South REC, Grant/Award Number: 10/H0305/83; Department of Health, Grant/Award Number: WT098051; Health Innovation Challenge Fund, Grant/Award Number: HICF‐1009‐003; Medical Research Council; Cancer Research UK; Wellcome Trust; National Institute for Health Research Funding information

Funding Information:
We would like to thank the patients and their families. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF‐1009‐003], a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute [grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Publisher Copyright:
© 2020 Wiley Periodicals LLC

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • SETD2
  • clinical genetics
  • genotype phenotype
  • histone modification
  • neurodevelopmental

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Genotype–phenotype correlation at codon 1740 of SETD2'. Together they form a unique fingerprint.

Cite this