A case report and review of the literature indicate that HMGA2 should be added as a disease gene for Silver-Russell syndrome

Abstract

Patients with Silver-Russell syndrome (SRS), a syndromic growth retardation syndrome, usually harbor an epimutation at chromosome 11p15 or a maternal uniparental disomy of chromosome 7. However, to date the genetic cause remains unknown in around 40% of SRS cases, suggesting genetic heterogeneity and involvement of other genes. We present a 4-year-old female patient with the clinical diagnosis of SRS and negative results in common genetic SRS diagnostics. Whole exome sequencing identified a de novo heterozygous 7.3 kb deletion on chromosome 12q14.3 including exon 1 and 2 of HMGA2. HMGA2 encodes an architectural transcription factor and has already been linked to body size variations in various genome-wide association studies and mouse models. Reviewing the literature, we found additional four patients with a phenotype of SRS harboring point mutations or structural variants involving HMGA2. We conclude that genetic testing of HMGA2 should be considered in routine diagnostics in patients with the suspicion of SRS.

Keywords: Differential diagnosis; Dna copy number variation; Dwarfism; Germ-line mutation; Sequence deletion; Whole exome sequencing.