ESPE Abstracts

Background: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with very close phenotypic (prenatal and postnatal growth retardation, early feeding difficulties, early puberty) and molecular anomalies. Our objective was to describe the clinical overlap between SRS and TS and to extensively study the molecular aspects of patients with 14q32.2 molecular disruption.

Patients: We identified 28 patients with disruption of the 14q32.2 imprinted region in our center. We retrospectively analyzed clinical data and performed extensive molecular analysis in these patients including multiloci methylation analysis and exome sequencing.

Results: A majority of patients (60.7%) showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region (IG-DMR) by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Netchine-Harbison SRS clinical scoring system was ≥4/6 and consistent with a clinical diagnosis of SRS in most patients (72.7%). Multiple methylation defects (MLMD) were identified in 58.8% of patients with MEG3/DLK1 epimutation. No correlation was found with the phenotype of the patients. No mutation, deletions or duplications of the 14q32.2 region were identified in patients with epimutation. Four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation were found by exome sequencing. Among these patients, one with MLMD affecting six loci aside from 14q32.2, inherited an unreported maternal variation in the ARID4A gene.

Conclusions: We provide clinical and molecular data to support that, as raised in the SRS international consensus, 14q32.2 disruption may be considered as an alternative molecular diagnosis of SRS. MEG3/DLK1:IG-DMR hypomethylation should be investigated in case of suspected SRS without chromosome 7 or 11p15 region anomalies. These clinical data encourage similar consideration and management for TS and SRS patients with a special attention to their young age at puberty onset and their early BMI increase. In case of MEG3/DLK1:IG-DMR hypomethylation identification, an additional molecular analysis must be carried out to identify any paternal deletion within the 14q32.2 region because of the different prognosis and management of these patients. The MLMD frequency being particularly high in this population and the absence of cis-regulatory element defects strongly suggest that these imprinting disturbances may be secondary to the dysfunction of one or several trans-acting factors.