ESPE Abstracts

Abnormal expression of imprinted genes leads to imprinting disorders (IDs). Silver-Russell syndrome (SRS) and Prader-Willi syndrome (PWS) are representative IDs showing small for gestational age and short stature (SGA-SS).Temple syndrome (TS14) caused by abnormal gene expression at the 14q32.2 imprinted region, maternal uniparental disomy of chromosome 6 (UPD(6)mat), 16 (UPD(16)mat), and 20 (UPD(20)mat) are also associated with SGA-SS. Fuethermore, some copy number variations (CNVs) cause SGA-SS. However, there is no systematic study about IDs and CNVs in a large SGA-SS cohort .

Subjects: This study included 346 patients with SGA-SS and no apparent chromosomal or monogenic disorders. Their birth weight and length were less than the 10th percentile, and their height was less than -2.0 SD at two years of age. Of them, 148 patients with four or more items of Netchine-Harbison clinical scoring system (NH-CSS) were classified as SRS-compatible group, and 49 patients with three items of NH-CSS together with triangular face and/or fifth finger clinodactyly were classified as SRS-like group. The remaining 149 patients were classified as non-SRS group.

Method: To detect genetic causes of these patients, we first performed methylation analysis using pyrosequencing for the PLAGL1-, PEG1/MEST-, PEG10-, H19-, Kv-, DLK1-MEG3 intergenic-, MEG3-, SNRPN-, ZNF597-, and GNAS A/B-DMRs. For patients with abnormal methylation of these DMRs, we performed microsatellite analysis to detect UPD and MS-MLPA and/or aCGH analysis using custom made arrays for imprinted regions to detect submicroscopic CNVs. Next, we conducted aCGH analysis using catalog arrays to detect CNVs causing monogenic disorders in patients with normally methylated DMRs.

Results: Hypomethylation of the H19-DMR (H19-hypo) and UPD(7)mat which are the main genetic causes of SRS were detected 39, 10, and 9 patients in SRS-compatible, SRS-like, and non-SRS group, respectively. IDs other than SRS were detected 17, 3, and 4 patients in SRS-compatible, SRS-like, and non-SRS groups. TS14, UPD(20)mat, UPD(6)mat, PWS, and UPD(16)mat were detected 12, 5, 2, and 2 patients in this cohort. Various CNVs causing monogenic disorders were detected 11, 7, and 9 patients in SRS-compatible, SRS-like, and non-SRS group.

Discussion: SGA-SS is a heterogeneous condition. This study showed that a part of SGA-SS is caused by imprinting defects other than H19-hypo and UPD(7)mat or CNVs related to monogenic disorders. Our results highlight the clinical importance of imprinting defects and CNVs as genetic causes of SGA-SS.