(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 three 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.
These 249 patients with SGA-SS were classified into ‘SRS-compatible group’ (n=148), ‘non-SRS with normocephaly or relative macrocephaly at birth group’ (non-SRS group) (n=94), or ‘non-SRS with relative microcephaly at birth group’ (non-SRS with microcephaly group) (n=7). The 44.6% of patients in ‘SRS-compatible group’, 21.3% of patients in ‘non-SRS group’, and 14.3% in ‘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, were detected in 30.4% of patients in ‘SRS-compatible group’ and in 13.8% of patients in ‘non-SRS group’.
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.