SQOR – Leigh syndrome

This summary reviews the evidence linking pathogenic variants in SQOR to Leigh syndrome. The association is based on clinical case reports and multi‐patient studies that detail consistent phenotypes including lactic acidosis and coma in affected individuals (PMID:32160317). The patients, drawn from two unrelated families, exhibit a classic mitochondrial disease presentation, which supports the diagnostic decision‑making process in metabolic disorders.

Assessment of clinical validity categorizes the gene‑disease association as Strong. In the reported studies, three probands (two siblings in one family and one unrelated case) presented with homozygous pathogenic variants in SQOR, with segregation observed in familial testing (PMID:32160317). Functional studies further confirmed markedly reduced enzyme activity and abnormal protein levels, thereby strengthening the evidence for causality.

Genetic evidence supports an autosomal recessive inheritance pattern where two distinct pathogenic variants were reported. The variant selected for this summary is: c.446del (p.Leu149ArgfsTer18). In addition to the selected variant, a recurrent founder mutation, c.637G>A (p.Glu213Lys), was identified in another family, providing independent validation of the variant spectrum in SQOR-associated Leigh syndrome (PMID:32160317).

Functional and experimental analyses demonstrate that SQOR deficiency leads to impaired hydrogen sulfide catabolism, resulting in complex IV inhibition and subsequent energy failure. Biochemical assays, including spectrophotometric enzyme activity measurement and western blotting, revealed severely diminished SQOR protein levels in patient tissues. These functional findings are fully concordant with the clinical phenotype of Leigh syndrome, supporting the mechanistic link between the genetic defect and mitochondrial dysfunction (PMID:32160317).

There is minimal conflicting evidence regarding the role of SQOR in Leigh syndrome despite additional functional studies exploring SQOR in disparate phenotypes such as osteoporosis and cardiometabolic heart failure. These alternative associations have been investigated independently and are considered distinct from the clearly delineated SQOR‐Leigh syndrome relationship. Thus, the focused evidence on Leigh syndrome remains robust and clinically actionable.

In conclusion, the integration of segregation data, genetic variant spectra, and functional studies strongly supports a causal role for homozygous SQOR variants in the pathogenesis of Leigh syndrome. This evidence not only enhances our diagnostic confidence but also highlights the potential for targeted therapeutic interventions in affected individuals.

References

• Journal of inherited metabolic disease • 2020 • Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease PMID:32160317

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