Molecular characterization of temple syndrome families with 14q32 epimutations

Temple Syndrome (TS14) is an imprinting disorder caused by molecular disruptions of the imprinted region in 14q32 (MEG3:TSS-DMR). The frequency of the three known TS14 subtypes (deletions, maternal uniparental disomy (upd(14)mat), loss of methylation (LOM)) is currently in discussion, and within the LOM group, the occurrence of Multilocus Imprinting Disturbances (MLID) has been identified. We present 16 TS14 patients with molecular alterations affecting the MEG3:TSS-DMR, comprising seven patients (43.8%) with LOM, six carriers with upd(14)mat (37.5%), and three cases (18.8%) with a deletion affecting the paternal MEG3:TSS-DMR. We did not find any evidence for MLID in the LOM group, including two cases in which different tissues were available. Whole exome sequencing (WES) in the MEG3:TSS-DMR LOM patients and their parents (Trio WES) did not reveal an obvious pathogenic variant which might cause aberrant methylation at imprinted loci. By summarizing our data with those from the literature, we could show that MLID affecting clinically relevant imprinted loci is rare in TS14 and therefore differs markedly from other imprinting disorders associated with MLID, e.g. Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). However, consistent with the clinical overlap with TS14, in SRS patients carrying MLID the MEG3:TSS-DMR is frequently affected. Variants in the known candidate genes for maternal effect variants causing MLID and fetal MLID determinants could not be identified in TS14 patients. Thus, 14q32 epimutations probably have other molecular causes than epimutations in BWS or SRS patients.