Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology.

Background: Recently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.

Objective: To clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.

Methods: We studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the :TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated :TSS-DMR.

Results: We identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.

Conclusion: We suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.