A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype

Agostina De Crescenzo, Valentina Citro, Andrea Freschi, Angela Sparago, Orazio Palumbo, Maria Vittoria Cubellis, Massimo Carella, Pia Castelluccio, Maria Luigia Cavaliere, Flavia Cerrato, Andrea Riccio

Research output: Contribution to journalArticlepeer-review


Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and post-natal growth retardation, dysmorphic facial features and body asymmetry. About 50% of the patients carry (epi)genetic alterations involving chromosomes 7 or 11.The high proportion of patients with unidentified molecular etiology suggests the involvement of other genes. Interestingly, SRS patients share clinical features with the 12q14 microdeletion syndrome, characterized by several deletions with a 2.6 Mb region of overlap. Among the genes present in this interval, high mobility AT-hook 2 (HMGA2) appears to be the most likely cause of the growth deficiency, due to its described growth control function. To define the role of HMGA2 in SRS, we looked for 12q14 chromosome imbalances and HMGA2 mutations 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). We identified a novel 7 bp intronic deletion in HMGA2 present in heterozygosity in the proband and her mother both displaying the typical features of SRS. We demonstrated that the deletion affected normal splicing, indicating that it is a likely cause of HMGA2 deficiency. This study provides the first evidence that a loss-of-function mutation of HMGA2 can be associated with a familial form of SRS. We suggest that HMGA2 mutations leading to haploinsufficiency should be investigated in the SRS patients negative for the typical 11p15 (epi)mutations and matUPD7.

Original languageEnglish
Pages (from-to)287-293
Number of pages7
JournalJournal of Human Genetics
Issue number6
Publication statusPublished - Jun 26 2015

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


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