ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
19298872 Buysse et al. (2009) report a 9-year-old male referred for idiopathic proportionate short stature with an intragenic deletion of HMGA2. Per the authors: "The first deleted oligonucleotide was located at 64.511 Mb in intron 2 and the last deleted oligonucleotide was located at 64.533 Mb in intron 3. The maximal deletion extends from 64.394 Mb (w110 kb upstream of HMGA2) to 64.568 Mb (intron 3)." The boy was said to have normal cognitive development with no dysmorphic features (outside of proportionate short stature) and no other health issues. Weight, height, and head circumference all measured at approximately 2 standard deviations from the mean. The deletion was found to be inherited from his mother (height -2.15 SD), and was also present in a maternal aunt (height -1.55 SD) and the maternal grandmother (height -1.81 SD). Of note, the authors also describe 5 other larger, de novo deletions that include HMGA2 (as well as other genes). Each of these patients were also described as having short stature.
25809938 De Crescenzo et al. 2015 describe a 4-year-old girl with short stature (height -2.9 SD) and dysmorphic features suggestive of Russell Silver syndrome with a 7bp deletion "eliminate[ing] the 3? AG acceptor site of the HMGA2 intron 4." This variant was also found in her affected mother (height -3.87 SD). A maternal aunt and the maternal grandfather were also said to be affected, but were unavailable for testing. The variant was detected after the authors sequenced the gene in a cohort of 45 patients "with growth retardation and SRS-like phenotype but no 11p15 (epi)mutations or maternal uniparental disomy of chromosome 7(matUPD7)." The authors performed additional studies (as described in the paper) to show that the variant did affect normal splicing.

Haploinsufficiency phenotype comments:

Deletions of the larger 12q14 region including HMGA2 (along with other genes) have been frequently reported (for example, PMIDs 26266063, 22987822, 22887875, etc.); short stature is a consistent phenotype reported in association with these deletions. Analyses of the smallest region of overlap among reported cases has suggested that HGMA2 is contributing to the short stature phenotype. The scoring here, however, is based upon observations of putative loss of function of this gene alone; current publicly available evidence supports a haploinsufficiency score of 2.

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