De novo truncating variant in NSD2gene leading to atypical Wolf-Hirschhorn syndrome phenotype

Abstract

Background Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome caused by partial 4p deletion highly variable in size in individual patients. The core WHS phenotype is defined by the association of growth delay, typical facial characteristics, intellectual disability and seizures. The WHS critical region (WHSCR) has been narrowed down and NSD2 falls within this 200 kb region. Only four patients with NSD2 variants have been documented with phenotypic features in detail. Case presentation Herein, we report the case of a 12-year-old boy with developmental delay. He had dysmorphic facial features including wide-spaced eyes, prominent nasal bridge continuing to forehead, abnormal teething and micrognathia. He also had mild clinodactyly of both hands. Using whole-exome sequencing, we identified a pathogenic mutation in NSD2 [c.4029_4030insAA, p.Glu1344Lysfs*49] isolated from peripheral blood DNA. Sanger confirmation of this variant revealed it as a de novo truncating variant in the family. Conclusion Here, we reported a boy with de novo truncating variant in NSD2 with atypical clinical features comparing with 4p16.3 deletion related WHS. Our finding further supported the pathogenesis of truncating variants in NSD2 and delineated the possible symptom spectrum caused by these variants.

The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy

“…Patients with deletions involving the 165 kb WHS critical region usually exhibit these typical features of WHS [4], but individuals with LOF mutations of NSD2 often do not present with the full WHS facial features [1,3,9]. They exhibited milder or less recognizable facial dysmorphism comparing to typical 4p16.3 deletion WHS patients [6,[8][9][10]15]. As the phenotypes of NSD2 patients did not meet the minimal diagnostic criteria for WHS [1,14], a new intellectual disability and short stature syndrome has been proposed for these patients [15].…”

“…NSD2 encodes nuclear receptor-binding set domain protein 2, a histone-lysine N-methyltransferase that is believed to play a significant role in normal development [5]. Since 2018, eight patients with loss of function NSD2 variants have been reported around the world [6][7][8][9][10] (Fig. 1).…”

Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing

“…A subsequent review of CMA data showed evidence of a deletion at that locus (Supplemental Figure 1B). However, the deletion was considered benign as it lay in a known complex region with common background CNV variation where other similar benign losses have been reported in ClinVar and Decipher (25)(26)(27). GS failed to call any variants here due to problems in read-mapping in the region.…”

Alternatively Splicing Interactomes Identify Novel Isoform-Specific Partners for NSD2

“…The nuclear receptor SET domain containing protein 2 ( NSD2 ), also known as MMSET or WHSC1 , is a member of the NSD protein family ( Allali-Hassani et al, 2014 ), which mainly catalyzes histone H3 lysine ( Huang et al, 2013 ; Poulin et al, 2016 ). NSD2 is a critical gene in the pathology of Wolf–Hirschhorn Syndrome (WHS; Jiang et al, 2019 ; McDevitt et al, 2019 ), a severe neurodevelopmental disorder characterized by distinctive developmental delays (DDs), intellectual disabilities (IDs), and seizures, which occur in more than 50% of WHS infants ( Deardorff and Zackai, 2007 ). The disease results from distal deletions on the short arm of chromosome 4 (chromosome 4p16.3) ( Descartes et al, 2017 ), which occurs in 1 in 50,000 births ( Deardorff and Zackai, 2007 ).…”