A novel syndrome caused by the constitutional gain-of-function variant p.Glu1099Lys in NSD2

Abstract

Purpose: NSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) region. Recent descriptions delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occures somatically in leukemia and has a gain-of-function (GoF) effect. Methods: We describe two unrelated individuals carrying c.3295G>A, p.Glu1099Lys as heterozygous de novo germline variants identified by exome sequencing of blood DNA and subsequently confirmed in two ectodermal tissues. We use omics data from the Cancer Cell Line Encyclopedia to analyze the GoF effect. Results: Clinically these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands and organomegaly. We confirmed increased K36me2 methylation in lines with either NSD2 GoF variants or duplications. Cells with GoF variants showed increased DNA promoter methylation and dysregulated RNA expression, influencing cellular modules involved in white blood cell activation, cell growth and organ development. Conclusion: NSD2 GoF caused by the missense variant p.Glu1099Lys leads to a novel syndromic phenotype distinct from both the previously described LoF phenotypes. Other variants causing NSD2 hyperactivation or overexpression may cause a similar phenotype. This syndrome should be distinguished from the recently named Rauch-Steindl syndrome caused by NSD2 haploinsufficiency.

Epigenomic Approaches for the Diagnosis of Rare Diseases

“…This overlap in phenotype is in contrast with alterations in the different members of the MLL family of H3K4 methyltransferases ( KMT2A-D, SET1A , and SET1B ) that cause different symptoms, suggesting that they play crucial yet non-redundant roles in the brain. Finally, both gain and loss-of-function mutations in NSD2 have been found in patients with intellectual disabilities [ 19 ].…”

“…Additionally, unexpected increases in mRNA levels have been reported for some mutant genes not producing proteins and might reflect a compensatory mechanism in response to absent protein [ 8 ]. RNA-seq has also been successfully used for variant calling [ 19 ]. This approach limits the detection of variants to genes that are expressed in the analyzed tissue and, therefore, is not intended to replace WGS or WES approaches but rather offer an alternative in cases where they are neither available nor cost-effective.…”