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.
INTRODUCTION
The Wnt ligand secretion mediator is encoded by WLS, and biallelic variants in this gene have been associated with an ultra-rare syndrome known as Zaki syndrome (ZKS). This study presents the fourteenth documented case of ZKS globally and reviews the clinical and genetic information of previously identified ZKS patients.
METHODS
A 17-year-old female from Iran underwent whole-exome sequencing due to a range of phenotypic symptoms suggestive of a unique syndrome. Sanger sequencing was employed to validate the candidate variant and to investigate its segregation among family members.
RESULTS
The patient was found to be homozygous for NM_024911.7: c.1433A>G, p.(Tyr478Cys) located in exon 11 of WLS. She represents the fifth ZKS patient identified with this variant, indicating a possible mutational hotspot. Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development. A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature. Nevertheless, challenges persist in diagnosing ZKS due to poorly defined genotype-phenotype correlations.
CONCLUSION
The clinical characteristics observed in our patient expand the phenotypic spectrum of ZKS. Additionally, the p.(Tyr478Cys) variant may represent a potential mutational hotspot within WLS.
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