A Homozygous Missense Variant in DCLK2 as a Potential Modifier of Disease Severity in PDHA1-Associated Primary Pyruvate Dehydrogenase Complex Deficiency

Introduction: Primary pyruvate dehydrogenase complex deficiency (PDCD) is a genetically heterogeneous mitochondrial disorder with marked clinical variability. PDHA1 is the most common cause of PDCD, but additional genetic factors may contribute to disease severity. Methods: A consanguineous family with two affected male siblings with clinical features of PDCD underwent clinical and genetic investigation. Whole-exome sequencing (WES), X-chromosome analysis, genome-wide autozygosity mapping, and segregation analysis were performed. Clinical, biochemical, neuroimaging, ophthalmological, and longitudinal medical records were reviewed. In silico analyses were performed for the identified variants. Results: Both siblings presented with neonatal lactic acidosis and severe neurological disease, including Leigh brain abnormalities, followed by progressive neuromuscular and multisystem manifestations. WES identified a novel hemizygous PDHA1 missense variant (c.754C>G; p.Leu252Val; rs1555934383), consistent with X-linked inheritance and providing the primary genetic explanation for PDCD. Autozygosity mapping identified a shared identical-by-descent interval on chromosome 4, within which a novel homozygous DCLK2 missense variant (c.101G>A; p.Ser34Asn) was identified. The variant was present in both affected siblings and segregated within the family. Despite sharing both variants, the siblings showed marked differences in disease severity. The younger sibling developed severe neurological and respiratory complications and died in childhood following a surgical procedure, whereas the older sibling survived into late adolescence but developed substantial neurological, metabolic, respiratory, and ophthalmological complications, including profound visual impairment and bilateral optic atrophy. Conclusions: The PDHA1 variant represents the primary genetic cause of PDCD, while the co-segregating homozygous DCLK2 variant is a candidate modifier of disease severity. Its localization within the shared IBD interval and biological relevance to neuronal stress responses support this hypothesis and suggest that DCLK2 may contribute to the phenotypic variability and severity of PDHA1-associated disease.