1. The constitutional gain-of-function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome
- Author
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Bernt Popp, Melanie Brugger, Sibylle Poschmann, Tobias Bartolomaeus, Maximilian Radtke, Julia Hentschel, Nataliya Di Donato, Andreas Rump, Janina Gburek‐Augustat, Elisabeth Graf, Matias Wagner, Ina Sorge, Johannes R Lemke, Thomas Meitinger, Rami Abou Jamra, Vincent Strehlow, and Theresa Brunet
- Subjects
SHORT REPORT ,SHORT REPORTS ,gain-of-function ,Glu1099Lys ,neurodevelopmental disorder ,NSD2 ,Rauch-Steindl syndrome ,Wolf-Hirschhorn syndrome ,Genetics ,Glu1099lys ,Nsd2 ,Rauch-steindl Syndrome ,Wolf-hirschhorn Syndrome ,Gain-of-function ,Neurodevelopmental Disorder ,Genetics (clinical) ,ddc - Abstract
NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) critical region. Recent descriptions have delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occurs somatically in leukemia and has a gain-of-function (GoF) effect. We describe two individuals carrying p.Glu1099Lys as heterozygous de novo germline variant identified by exome sequencing (ES) of blood DNA and subsequently confirmed in two ectodermal tissues. Clinically, these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands, and organomegaly. Public cell lines with NSD2 GoF variants had increased K36me2, DNA promoter methylation, and dysregulated RNA expression. NSD2 GoF caused by p.Glu1099Lys is associated with a novel phenotype different from WHS and Rauch-Steindl syndrome (RAUST).
- Published
- 2021