NSD2

Inheritance Pattern: AD

Disease ID:MONDO:0859219

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0859219

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0859219

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008684

Submitter: Illumina

NSD2 was first reported in relation to autosomal dominant NSD2-Wolf-Hirschhorn syndrome in 2017 (28600779: Monies et al. 2017). At least six unique de novo, loss-of -function variants have been reported in the literature. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands from three publications (29892088: Derar et al. 2018; 29760529: Lozier et al. 2018; 31171569: Barrie et al. 2019). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is loss of function (31171569: Barrie et al. 2019). This gene-disease relationship is supported by expression studies, which show that fetal brain contained the most complex pattern of transcripts and is expressed in mouse brain, ganglia, neural tube, jaw, frontal face region, intestinal and lung epithelium, liver, adrenals, and the urogenital system (9618163: Stec et al. 1998). In addition, Whsc1-deficient heterozygote mice present with severe growth and craniofacial defects (19483677: Nimura et al. 2009). In summary, NSD2 is definitively associated with autosomal dominant NSD2-Wolf-Hirschhorn syndrome.

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Although *de novo* truncating variants in *NSD2* had been identified in large exome sequencing studies in autism spectrum disorder and intellectual disability as early as 2014 (PMIDs: 25363760, 28135719), the first report focusing on *NSD2* variants as a cause of autosomal dominant syndromic intellectual disability was published in 2018 (Lozier et al., PMID: 29760529). Since then, more than 40 patients with neurodevelopmental abnormalities have been reported with primarily *de novo* variants in *NSD2* and a few reported cases of variants inherited from an affected parent (PMIDs: 25363760, 28135719, 28600779, 29760529, 29892088, 30345613, 31171569, 31382906, 33941880). Zanoni et al. (2021, PMID: 33941880) described a cohort of 18 previously unreported patients with *NSD2* pathogenic variants. Patients shared a phenotype characterized by developmental delay, prenatal-onset growth retardation and low birth weight, feeding difficulties, failure to thrive, height and head circumference below the 5th centile (<−1.65 SD), hypotonia, dysmorphic features, usually mild intellectual disability, and autistic features. *NSD2* is located in the Wolf-Hirschhorn syndrome critical region; NSD2 deficiency leads to a distinct and milder phenotype that only partially overlaps with Wolf-Hirschhorn syndrome. The majority of variants identified to date are nonsense and frameshift variants that result in predicted loss-of-function of NSD2. Additionally, this is a highly constrained gene with few loss-of-function variants reported in public databases. Consequently, the mechanism of disease is hypothesized to be haploinsufficiency of *NSD2* due to loss-of-function or hypomorphic variants. *NSD2* encodes a histone methyltransferase involved in transcriptional regulation. Experimental evidence showed that cells with *NSD2* missense variants have reduced H3K36me2 methylation levels and impaired ability to rescue methylation abnormalities in NSD2-depleted cells (PMID: 33941880). In summary, there is definitive evidence supporting the relationship between *NSD2* and autosomal dominant syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 2, 2021 (SOP Version 8).