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The association between CRLS1 (HGNC:16148) and Leigh syndrome (MONDO:0009723) has been reported in a consanguineous Moroccan family with multiple affected siblings (PMID:19542079). In this family of 11 children, three were affected, and genetic analysis revealed homozygosity for a CRLS1 variant alongside candidate variants in other genes. The reported CRLS1 variant, c.578C>T (p.Pro193Leu), was observed in the affected individuals; however, its presence in approximately 20% of the local control population and only a 50% reduction in enzyme function call into question its pathogenic role (PMID:19542079).
Genetic evidence is limited by the single-family observation with modest segregation data. Despite the variant being homozygous in the affected members and the family displaying an autosomal recessive inheritance pattern, the allele frequency in controls undermines its relevance as a monogenic cause for a rare disorder such as Leigh syndrome. In addition, while a second study identified the same variant in a similar clinical setting, the overlap with variants in other candidate genes further complicates the interpretation.
Functional studies in the report demonstrated altered complex I assembly, with patients exhibiting only 30–40% of mature complex I compared to 70–90% in unaffected carriers (PMID:19542079). Although these cellular findings support a potential role for CRLS1 in mitochondrial bioenergetics, the modest reduction in enzyme activity suggests that the variant's functional impact may not fully explain the severe phenotype observed in Leigh syndrome.
There is an apparent discordance between the genetic and functional data. While the in vitro findings provide some insight into the molecular defect, the high allele frequency and partial loss of function weaken the clinical validity of the CRLS1–Leigh syndrome association. The evidence remains insufficient to definitively establish causality, and further investigation is warranted to reconcile these discrepancies.
Overall, the currently available evidence classifies the association between CRLS1 and Leigh syndrome as disputed. Although functional assays indicate a biological effect on complex I assembly, the genetic data are not robust enough to support CRLS1 as a sole driver of the phenotype in Leigh syndrome.
Key Take‐home Sentence: The current genetic and functional evidence for a CRLS1 involvement in Leigh syndrome is disputed, highlighting the need for additional studies to clarify its clinical relevance.
Gene–Disease AssociationDisputedAlthough the c.578C>T (p.Pro193Leu) variant was observed in affected individuals from a consanguineous family (PMID:19542079), its high allele frequency in controls (20%) and only moderate reduction in enzyme activity undermine a definitive association with Leigh syndrome. Genetic EvidenceLimitedThe genetic evidence is limited to a single family with modest segregation data, and the recurrence of the variant in a multi‐patient context is confounded by its presence in controls (PMID:19542079). Functional EvidenceModerateFunctional assays demonstrated altered complex I assembly with patients showing 30–40% of mature complex I compared to 70–90% in carriers, providing moderate support for a biochemical defect; however, the relatively small magnitude of enzyme reduction diminishes the claim for causality (PMID:19542079). |