Monoallelic SH2B1 Variants in Neurodevelopmental Disorders: Phenotypic Expansion and Functional Characterization of...

SH2B1 encodes an adaptor protein involved in metabolic regulation and body-weight control. Although SH2B1 haploinsufficiency is a recognized contributor to obesity in 16p11.2 deletion syndrome, the relationship between rare monoallelic SH2B1 variants and neurodevelopmental disorders (NDDs) remains poorly characterized.

We analyzed genetic and clinical data from a cohort of individuals with NDDs. The identified rare SH2B1 variants were evaluated using bioinformatic tools and structural modeling. Functional consequences were assessed in vitro through analyses of protein expression, subcellular localization, and extracellular signal-regulated kinase (ERK) pathway activation via EGF stimulation assays.

Five individuals carrying rare monoallelic SH2B1 variants presented with syndromic NDDs, including developmental delay, intellectual disability, autism spectrum disorder, dysmorphic features, and hyperphagia. Whole-exome sequencing identified five heterozygous SH2B1 variants, including three missense variants (c.52C>G, p.Leu18Val; c.696A>T, p.Arg232Ser; c.1141C>T, p.Pro381Ser) and two truncating variants (c.90_91delTG, p.Cys30Ter; c.121_130dup, p.Arg44LeufsTer30); four of these arose de novo, whereas c.696A>T (p.Arg232Ser) was maternally inherited. The individual carrying the maternally inherited p.Arg232Ser variant presented with elevated BMI and hyperphagia. In overexpression assays, truncating variants showed reduced protein expression and abnormal subcellular localization, whereas missense variants retained comparable protein levels but showed increased EGF-induced ERK phosphorylation in vitro, suggesting altered ERK signaling responses.

This study further delineates the clinical spectrum associated with rare monoallelic SH2B1 variants in individuals with NDDs. Functional analyses suggest variant-specific effects on protein expression, subcellular localization, and ERK signaling responses. These findings support the consideration of SH2B1 in genetic analyses of NDDs, particularly in individuals with co-occurring metabolic abnormalities.