The genotypic and phenotypic landscape of <i>PDHA1</i> -related pyruvate dehydrogenase complex deficiency

This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015 - SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping…