ARL2 – MRCS syndrome

A de novo variant in ARL2 was identified through whole‑exome sequencing in a Chinese pedigree with MRCS syndrome (PMID:30945270), providing strong evidence of a gene‑disease association. The clinical presentation includes cataract, rod‑cone dystrophy, posterior staphyloma, and microcornea, which are consistent with the MRCS phenotype.

Genetic evidence is underscored by the identification of the heterozygous variant c.44G>T (p.Arg15Leu) in the proband. Segregation analysis confirmed its de novo occurrence, as the variant was absent in both parental samples (PMID:30945270). This finding supports a pathogenic role for ARL2 in MRCS syndrome.

The variant c.44G>T (p.Arg15Leu) disrupts a highly conserved residue, and its functional impact was confirmed via co‑immunoprecipitation and immunoblotting assays, which demonstrated a 62% reduction in binding affinity for HRG4 (PMID:30945270). This alteration likely contributes to mitochondrial dysfunction, a process that has been mechanistically linked to the retinal degeneration observed in patients.

Extensive functional studies, including immunofluorescence localization and transgenic mouse models, recapitulated key aspects of the MRCS phenotype. In addition, complementary research on ARL2’s modulation of tubulin‑folding cofactor D in cellular systems (PMID:10831612) further supports the role of ARL2 in maintaining cellular homeostasis, thereby strengthening the functional evidence for its involvement in disease.

In summary, the convergent genetic and experimental findings firmly position ARL2 as a strong candidate gene for MRCS syndrome. The evidence not only exceeds the ClinGen scoring criteria but also offers a robust framework for clinical diagnostics, commercial assay development, and future research. Key take‑home: The de novo c.44G>T (p.Arg15Leu) variant in ARL2 provides a definitive diagnostic marker for MRCS syndrome through combined genetic and functional validation.

References

• Clinical genetics • 2019 • Whole‑exome sequencing identified ARL2 as a novel candidate gene for MRCS syndrome PMID:30945270
• The Journal of cell biology • 2000 • ADP ribosylation factor‑like protein 2 regulates the interaction of tubulin‑folding cofactor D with native tubulin PMID:10831612

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