A Candidate MEST Splice-Site Variant in a Patient with Silver–Russell Syndrome-like Phenotype: First Report and Literature Review
TL;DR
MEST is identified as a plausible candidate gene for SRS and provides a rationale for further functional studies, including in silico predictions and clinical correlation.
Abstract
Silver–Russell syndrome (SRS) is most commonly caused by epigenetic alterations at 11p15.5 or maternal uniparental disomy of chromosome 7 [upd(7)mat], though other molecular mechanisms remain unclear. While microdeletions encompassing MEST have been associated with SRS-like phenotypes, no pathogenic intragenic MEST variants have been reported to date. We describe a 6-month-old male infant with clinical features suggestive of a SRS-like phenotype, including intrauterine and postnatal growth restriction, triangular facies, prominent forehead, and small extremities. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) revealed neither methylation abnormalities at 11p15.5, 7p13, or 7q32 nor copy number variations (CNVs) in these regions. Trio whole-exome sequencing (trio-WES) identified a paternally inherited splice-site variant (c.890 + 1G > A) in MEST. Given the paternal-specific expression of MEST, this variant resides on the functionally active allele. Based on in silico predictions and clinical correlation, this case identifies MEST as a plausible candidate gene for SRS and provides a rationale for further functional studies. Phenotypic variation exists across molecular subtypes, yet definitive genotype–phenotype correlations await larger, systematically ascertained cohorts.