PDHX – Leigh syndrome

Biallelic loss-of-function variants in PDHX, encoding the E3‐binding protein of the pyruvate dehydrogenase complex, cause autosomal recessive Leigh syndrome. Whole exome sequencing of a patient with Leigh-like presentation revealed a homozygous nonsense variant c.1336C>T (p.Arg446Ter) in PDHX, with no additional affected relatives reported (PMID:30981218). No segregation data beyond the single proband are available, and direct functional assays of the PDHX variant were not performed; rescue studies of a co‐identified TIMMDC1 variant confirmed that PDHX deficiency underlies the clinical phenotype.

Key Take-home: Consider biallelic PDHX truncating variants in the diagnostic evaluation of autosomal recessive Leigh syndrome.

References

• Human mutation • 2019 • A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant. PMID:30981218

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