Relevance to Autism

De novo likely gene-disruptive (dnLGD) variants in the NSD2 gene have been identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), an ASD proband from the SPARK cohort (Wang et al., 2020), and three probands from the Deciphering Developmental Disorders study in 2017, while de novo missense variants in this gene have been observed in an ASD proband from a multiplex family from the AGRE cohort (Yuen et al., 2017) and a proband with intellectual disability (Lelieveld et al., 2016). Single-molecular molecular inversion probe (smMIP) sequencing of 3,363 probands from cohorts with a primary diagnosis of ASD in Wang et al., 2020 identified three ASD-associated likely-gene disruptive variants and five ASD-associated missense variants with CADD scores 30 in the NSD2 gene. NSD2 is located with the critical region of Wolf-Hirschhorn syndrome (WHS), and numerous studies have reported that de novo truncating variants in this gene recapitulate many WHS-associated phenotypes (Boczek et al., 2018; Derar et al., 2019; Barrie et al., 2019; Jiang et al., 2019). Zanoni et al., 2021 reported 18 previously unpublished individuals from 16 families with ultrarare pathogenic or likely pathogenic variants in NSD2 that presented with a core phenotype characterized by mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from those observed in individuals with Wolf-Hirschhorn syndrome; seven of these individuals presented with either a diagnosis of autism spectrum disorder or autistic features, and both individuals diagnosed with autism spectrum disorder in this report had de novo missense variants that were experimentally shown to reduce methylation activity and fail to reconstitute H3K36me2 levels in NSD2 knockout cells.

Molecular Function

This gene encodes a protein that contains four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain, and a PHD-type zinc finger. It is expressed ubiquitously in early development. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene maps to the 165 kb WHS critical region and has also been involved in the chromosomal translocation t(4;14)(p16.3;q32.3) in multiple myelomas.

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