Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

Abstract

Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

Response to Cueto-González et al

“…The phenotype of the affected individual, characterized by stature below the familial targetheight, occipitofrontal circumference in the lower-normal range, and mild to moderate intellectual disability without epilepsy, is in line with that of the patients described in our series. 1 As shown in our publication (see Figure 3B in Zanoni et al 1 ) and further emphasized by Cueto-González et al (Cueto-González AM, Fernández-Álvarez P, Valenzuela Palafoll I, Lasa-Aranzasti A, Vendrell-Bayona T, Tizzano E. Genetics in medicine. Genet Med.…”

Correspondence on “Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype” by Zanoni et al

“…Anna M a . Cueto-González 1,2,3,* Paula Fernández-Álvarez 1,2 Irene Valenzuela Palafoll 1,2,3 Amaia Lasa-Aranzasti 1,2 Teresa Vendrell Bayona 1,2 Eduardo F. Tizzano…”

“…Although seizures occur in >90% of patients with WHS (with onset within the first 3 years of life), it is very rare in patients with NSD2-related disorders, with only 2 cases reported in the Zanoni series (patient 10-I with multiple feverrelated seizures up to 8 years and patient 15-I with electroencephalogram findings showing epileptic activity in the absence of clinical seizures). 1,2 We found another published family with NSD2 variants, not included in the Zanoni series, whose index case had mild facial features, mild intellectual disability, growth retardation, and microcephaly without seizures. Interestingly, his father carrying the same NSD2 variant showed mild intellectual disability presenting a seizure after a fever episode as a child, during which encephalitis was suspected, but no definite diagnosis was made.…”

“…With great interest, we read the publication by Zanoni et al 1 about the loss-of-function and missense variants in NSD2 gene and the distinct developmental phenotype. We would like to draw attention toward NSD2 involvement and seizures related to Wolf-Hirschhorn syndrome (WHS) (OMIM 194191, ORPHA 280).…”

“…Slow weight gain is seen in 62.5% (20/32) of patients with NSD2-related disorders in comparison with 80% of patients with WHS; microcephaly (described as <2 SD or fifth percentile) is also present in 62.5% (20/32) of NSD2-related disorder cases in comparison with 80% of WHS cases. 1,2 Of the most important differences, patients with NSD2-related disorders present milder intellectual disability, and very few cases present with seizures. Although seizures occur in >90% of patients with WHS (with onset within the first 3 years of life), it is very rare in patients with NSD2-related disorders, with only 2 cases reported in the Zanoni series (patient 10-I with multiple feverrelated seizures up to 8 years and patient 15-I with electroencephalogram findings showing epileptic activity in the absence of clinical seizures).…”