Abstract
Maternal uniparental disomy 14 (UPD(14)mat) and related (epi)genetic aberrations affecting the 14q32.2 imprinted region result in a clinically recognizable condition which is recently referred to as Temple Syndrome (TS). Phenotypic features in TS include pre- and post-natal growth failure, prominent forehead, and feeding difficulties that are also found in Silver–Russell Syndrome (SRS). Thus, we examined the relevance of UPD(14)mat and related (epi)genetic aberrations to the development of SRS in 85 Japanese patients who satisfied the SRS diagnostic criteria proposed by Netchine et al and had neither epimutation of the H19-DMR nor maternal uniparental disomy 7. Pyrosequencing identified hypomethylation of the DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the MEG3-DMR in two cases. In both cases, microsatellite analysis showed biparental transmission of the homologs of chromosome 14, with no evidence for somatic mosaicism with full or segmental maternal isodisomy involving the imprinted region. FISH and array comparative genomic hybridization revealed neither deletion of the two DMRs nor discernible copy number alteration in the 14q32.2 imprinted region. Methylation patterns were apparently normal in other six disease-associated DMRs. In addition, a thorough literature review revealed a considerable degree of phenotypic overlap between SRS and TS, although body asymmetry was apparently characteristic of SRS. The results indicate the occurrence of epimutation affecting the IG-DMR and the MEG3-DMR in the two cases, and imply that UPD(14)mat and related (epi)genetic aberrations constitute a rare but important underlying factor for SRS.
Highlights
Human chromosome 14q32.2 harbors an imprinted region with several paternally expressed genes such as DLK1 and RTL1 and maternally expressed genes such as MEG3 and RTL1as, together with the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the post fertilization-derived secondary MEG3-DMR.[1,2] Consistent with this, maternal uniparental disomy 14 (UPD(14)mat) results in clinically discernible features such as pre- and post-natal growth failure, characteristic face with prominent forehead and micrognathia, small hands, muscular hypotonia, and precocious puberty.[3]
The MIs in case 1 were around the lower limit of the MIs in the six UPD(14)mat patients and much lower than the reference range in the 50 control subjects, whereas the MIs in case 2 were above the maximum MIs in the six UPD(14)mat patients, except for the MI of CG4, and below the reference range in the 50 controls, except for the MI of CG3
The present study showed that the IG-DMR and the MEG3-DMR were severely hypomethylated in case 1 with the MIs comparable to those of UPD(14)mat and moderately hypomethylated in case 2 with the MIs between those of UPD(14)mat patients and those of control subjects, in the absence of UPD(14)mat and microdeletion or copy number alteration involving the DMRs
Summary
Human chromosome 14q32.2 harbors an imprinted region with several paternally expressed genes such as DLK1 and RTL1 and maternally expressed genes such as MEG3 and RTL1as, together with the germline-derived primary DLK1-MEG3 intergenic differentially methylated region (IG-DMR) and the post fertilization-derived secondary MEG3-DMR.[1,2] Consistent with this, maternal uniparental disomy 14 (UPD(14)mat) results in clinically discernible features such as pre- and post-natal growth failure, characteristic face with prominent forehead and micrognathia, small hands, muscular hypotonia, and precocious puberty.[3]. We studied six UPD(14)mat patients for comparison and 50 control subjects to define the reference ranges of MIs. When hypomethylation was identified, we performed microsatellite analysis for nine loci on chromosome 14, FISH analysis for the IG-DMR and the MEG3-DMR, and array comparative genomic hybridization for the 14q32.2 imprinted region using a custom-build oligo-microarray containing 12 600 probes (Agilent Technologies, Palo Alto, CA, USA).[22] We performed pyrosequencing for the H19-DMR (ICR1) and the PEG1/MEST-DMR to re-confirm the absence of the known causes for SRS, and for the KvDMR (ICR2), the SNRPN-DMR, the PLAGL1DMR, and the GNAS exon A/B-DMR to examine the occurrence of Figure 1 Representative molecular findings. Primers utilized in this study are shown in Supplementary Table 1
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