The constitutional gain‐of‐function variant p.Glu1099Lys in NSD2 is associated with a novel syndrome

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).

Leveraging cancer mutation data to predict the pathogenicity of germline missense variants

“…15,16 These Mendelian disorders may or may not include cancer as a major phenotypic feature. 5,[17][18][19][20][21] Walsh and colleagues previously explored the use of cancer mutational hotspots data for interpreting germline variants in genes causing cancer predisposition syndromes. 12 However, when and to what extent cancer driver mutations are pathogenic in germline contexts, for rare Mendelian disorders in general, remains unknown.…”