EIF4A3 – Richieri Costa-Pereira syndrome

This summary describes the association between EIF4A3 and Richieri Costa-Pereira syndrome, a rare autosomal recessive acrofacial dysostosis. The syndrome is characterized by a spectrum of craniofacial and skeletal anomalies, including Pierre-Robin sequence, cleft mandible, abnormalities of the limbs, larynx, skeletal system, and microcephaly (PMID:29112243, PMID:29863549).

Genetic evidence supporting this association is robust. Multiple studies have documented biallelic pathogenic alterations in EIF4A3, with probands identified carrying a recurrent 16-repeat expansion in the 5′ untranslated region and a point mutation in trans observed in a mildly affected patient (PMID:29112243). In addition, a cephalometric study of nine individuals provided further corroboration of the underlying genotype–phenotype link (PMID:29863549). Segregation data, including the observation of an affected sibling in one family, additionally strengthens this gene–disease relationship.

While no classical coding sequence variant with a complete HGVS notation was explicitly reported within the published cases, the literature consistently reports a repeat expansion mechanism. This expansion is posited to disrupt the normal regulation of EIF4A3, likely leading to diminished expression and subsequent clinical manifestation of the syndrome. Based on the aggregate data, the genetic evidence is assigned a strong rating.

Functional studies of EIF4A3 have provided critical insights into its biological role. Multiple in vitro and in vivo experiments demonstrate that EIF4A3 is essential for exon junction complex assembly and proper functioning of nonsense‑mediated mRNA decay (PMID:16495234, PMID:23236153). These studies, although not exclusively performed in a RCPS context, support a loss‑of‑function disease mechanism that aligns with the recessive inheritance pattern observed in Richieri‑Costa‑Pereira syndrome.

Some variability in the clinical presentation has been reported, such as cases with a less severe phenotype or absence of a cleft mandible, suggesting that additional genetic modifiers or environmental factors may influence expressivity. However, this phenotypic heterogeneity does not detract from the strong overall clinical validity of the association.

In conclusion, the integration of genetic and functional evidence establishes a clear and strong association between EIF4A3 pathogenic alterations and Richieri‑Costa‑Pereira syndrome. This supports the clinical utility of incorporating EIF4A3 testing in diagnostic workflows for patients with overlapping craniofacial and skeletal anomalies, thereby enhancing diagnostic precision and enabling improved patient management.

References

• Clinical genetics • 2018 • Richieri-Costa-Pereira syndrome: Expanding its phenotypic and genotypic spectrum PMID:29112243
• The Journal of craniofacial surgery • 2018 • Cephalometric Findings in Nine Individuals With Richieri-Costa-Pereira Syndrome PMID:29863549
• RNA (New York, N.Y.) • 2006 • Mutational analysis of human eIF4AIII identifies regions necessary for exon junction complex formation and nonsense-mediated mRNA decay PMID:16495234
• Proceedings of the National Academy of Sciences of the United States of America • 2012 • Human spliceosomal protein CWC22 plays a role in coupling splicing to exon junction complex deposition and nonsense-mediated decay PMID:23236153

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