HMGA2 variants in Silver-Russell syndrome: homozygous and heterozygous occurrence.

CONTEXT: Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder, associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about half of patients currently remain without molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling. OBJECTIVE: Aim of the study was to corroborate the role of HMGA2 as SRS causing gene and reevaluate its mode of inheritance. DESIGN, SETTING, PATIENTS: Patients were part of an ongoing study aiming on SRS causing genes. They were classified according to the Netchine-Harbison clinical scoring system, DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before. RESULTS: Three novel pathogenic HMGA2 variants were identified in five patients from three SRS families, and fulfilling diagnostic criteria of SRS. For the first time homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in one patient, while all other did not receive growth hormone and stayed small. One patient developed a type 2 diabetes at age of 30 years. CONCLUSIONS: Identification of novel pathogenic variants confirms HMGA2 as a SRS causing gene, thus HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.