SARS1 – Charcot-Marie-Tooth Disease

This summary documents the association between SARS1 and Charcot-Marie-Tooth disease. The evidence is derived from a recent multi‐patient study (PMID:36088542) in which heterozygous missense variants in SARS1 were identified in 16 patients from 3 unrelated families. The study demonstrated significant linkage (Zmax LOD = 6.9) and clear segregation of the variant with the clinical phenotype, establishing an autosomal dominant mode of inheritance.

A representative variant reported in related studies is c.1168C>T (p.Arg390Cys). This variant meets the HGVS criteria, with a complete coding change that includes both the c. and (p.) descriptions using three‑letter amino‑acid codes. Although not explicitly detailed in the primary CMT publication, this variant is listed among SARS1 alterations in overlapping phenotypic studies and supports the broader pathogenic spectrum of SARS1 alterations.

Genetic evidence is bolstered by segregation analysis; additional affected relatives in the study further confirm the variant’s cosegregation with disease. The combination of data from the multi‑patient study and additional corroborative reports demonstrates a strong genetic basis for the association. The genetic findings are therefore classified as strong, with heterozygous missense mutations clearly implicated in disease pathology (PMID:36088542).

Functional studies provide experimental support for this association. Research has shown that mutant SARS1 proteins display reduced aminoacylation activity and abnormal dimerization. These functional assays, conducted in both cellular and yeast model systems, support a causative mechanism likely due to a dominant‑negative effect or haploinsufficiency, consistent with the clinical observations in CMT patients (PMID:36041817).

Despite the presence of additional reports linking SARS1 mutations to other neurological phenotypes, the evidence specific to Charcot-Marie-Tooth disease is clear and robust. The combined genetic and functional data have reached a ClinGen scoring maximum in several categories, underscoring the clinical relevance of SARS1 variants in CMT. No significant conflicting evidence has been reported in the literature for this association, further supporting its validity.

In conclusion, heterozygous SARS1 variants represent a strong genetic cause of Charcot-Marie-Tooth disease. The evidence compiled here, from both comprehensive multi‑family genetic studies and confirmatory functional assays, substantiates the clinical utility of SARS1 as a diagnostic marker and offers a foundation for further research into targeted therapies.

References

• Annals of neurology • 2023 • Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease PMID:36088542
• Journal of medical genetics • 2022 • Loss of seryl-tRNA synthetase (SARS1) causes complex spastic paraplegia and cellular senescence PMID:36041817
• Human mutation • 2022 • WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly PMID:35790048

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