ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
23160192 Doche et al. 2013: Describes 4 heterozygous variants (1 frameshift and 3 missense) in SH2B1 detected in 5 apparently unrelated individuals of mixed European descent amongst a cohort of 300 individuals with severe, early-onset obesity with a disproportionate degree of insulin resistance for their obesity. Mutations in genes causing known monogenic obesity syndromes had been excluded in these patients. All variants were inherited from overweight/obese parents. Individuals with SH2B1 variants were reported to have delayed speech development and aggressive behavior, but no formal psychiatric/behavioral observation was performed. The variants and the reported behavioral abnormalities were not detected amongst 500 control subjects. Subsequent functional studies demonstrated loss-of-function in assays of GH/NGF-mediated signaling.

Haploinsufficiency phenotype comments:

Of note, Pearce et al. (2014) (PMID: 24971614) describe 4 additional SH2B1 variants in 500 additional individuals from the same cohort of severe early-onset individuals used in the Doche et al. (2013) paper referenced above. Of these 4 new variants, only 1, T546A, lies within the same N-terminal region common to all 4 SH2B1 isoforms as the variants described in Doche et al. This variant was found in a single individual who was described as also having mild developmental delay. The other 3 variants are in the C-terminal tail of SH2B1 alpha; individuals with these variants were not reported to have neurodevelopmental phenotypes, and 2 of them have been observed in publically available exome databases (though BMI information is not available on these reportedly normal individuals). The authors suggest that "SH2B1 contains a spectrum of common and rare alleles that contribute to BMI and obesity predisposition with a broad range of penetrance, from low to more highly penetrant rare alleles." They also point out the "need to determine, at the mechanistic level, whether the behavioral phenotype results from disruption of a specific SH2B1 isoform (eg, SH2B1?) or a function emanating from the 1?631 region shared by all 4 isoforms." PMID: 17235396 Ren et al (2007) generated Sh2b1-knockout mice that developed hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of Sh2b1 corrected the metabolic disorders in the knockout mice and improved leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Neuron-specific overexpression of Sh2b1 dose-dependently protected against high fat diet-induced leptin resistance and obesity. They suggested that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity