SLCO5A1 and mesomelia‑synostoses syndrome

The association between SLCO5A1 and mesomelia‑synostoses syndrome (MSS) is supported by multiple independent studies reporting recurrent deletions that consistently encompass the SLCO5A1 locus. Although these deletions invariably include the neighboring SULF1 gene, the evidence indicates that the region, when disrupted, is associated with the characteristic skeletal phenotype of mesomelia (HP:0003027). This structural alteration acts in an autosomal dominant manner (PMID:20602915).

In a multi‐patient study, five unrelated probands from four distinct families harbored interstitial deletions spanning 582–738 Kb that included SLCO5A1. These deletions were detected with high‐resolution array comparative genomic hybridization and supported the critical involvement of this genomic region in disease pathogenesis (PMID:20602915).

A separate case report described an 11‐year‑old patient with multiple congenital anomalies including mesomelic limb shortening, in whom a novel 590 kb deletion was detected. Breakpoint analyses in this patient revealed non‐allelic homologous recombination mediated by LINE‑1 elements, further expanding the mutational mechanism that may contribute to MSS. This observation reinforces the clinically significant overlap between the affected region and the SLCO5A1 gene (PMID:28328141).

While a study reporting a de novo reciprocal translocation emphasized SULF1 haploinsufficiency, the disrupted topological associated domain (TAD) raises the possibility that altered regulation of SLCO5A1 might also contribute to the overall phenotype. Thus, even though isolated sequence variants in SLCO5A1 have not been reported, the consistent inclusion of this gene in pathogenic deletions across different studies provides genetic evidence in support of its role in MSS (PMID:38992676).

Functional assessments to date have not isolated SLCO5A1-specific pathogenic mechanisms. The gene’s contribution is inferred from the contiguous deletion model, where altered regulatory landscapes may result in ectopic enhancer adoption. In this context, the absence of direct functional assays constitutes a limitation, with functional evidence for SLCO5A1 being deemed limited compared to the robust genetic findings.

Integrating both genetic and experimental observations, the recurrent deletion events implicating the SLCO5A1 region establish a strong correlation between gene disruption and mesomelia‑synostoses syndrome. While additional functional studies are needed to delineate a gene‑specific mechanism, the current evidence provides a clinically useful framework for diagnosis and underscores the potential for this locus to serve as a target for further research.

References

• American journal of human genetics • 2010 • Mesomelia‑synostoses syndrome results from deletion of SULF1 and SLCO5A1 genes at 8q13 PMID:20602915
• American journal of medical genetics. Part A • 2017 • A 590 kb deletion caused by non‑allelic homologous recombination between two LINE‑1 elements in a patient with mesomelia‑synostosis syndrome PMID:28328141
• Molecular cytogenetics • 2024 • Mesomelia‑synostoses syndrome: contiguous deletion syndrome, SULF1 haploinsufficiency or enhancer adoption? PMID:38992676

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