Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

Abstract

Background: (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes.

Subjects and methods: To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis.

Results: These 249 patients with SGA-SS were classified into the "SRS-compatible group" (n = 148), the "non-SRS with normocephaly or relative macrocephaly at birth group" (non-SRS group) (n = 94), or the "non-SRS with relative microcephaly at birth group" (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the "SRS-compatible group," 21.3% of patients in the "non-SRS group," and 14.3% in the "non-SRS with microcephaly group" had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the "SRS-compatible group" and in 13.8% of patients in the "non-SRS group."

Conclusion: We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.

Keywords: SGA; Silver-Russell syndrome; imprinting disorder; short stature.

Figure 1.

Inclusion criteria for this study. Abbreviations: BL, birth length; BW, birth weight; NH-CSS, Netchine-Harbison clinical scoring system; PCNV, pathogenic copy number variants; SDS, standard deviation score; SGA-SS, short children born small-for-gestational-age; SRS, Silver-Russell syndrome.

Figure 2.

The frequency of etiologies in each subgroup. The red, yellow, green, and gray rectangles represent the frequency of H19LOM, UPD(7)mat, imprinting disorders other than H19LOM and UPD(7)mat, and unknown etiologies. H19LOM, loss of methylation of the H19/IGF2:intergenic differentially methylated region; UPD(7)mat, uniparental disomy chromosome 7.