新規二アレル性LIG3変異による免疫不全を伴う致死性表現型の原因究明

Pathogenic, biallelic variants in LIG3 are known to cause Mitochondrial DNA Depletion syndrome 20 with variable expression and severity. We describe a child with progressive encephalopathy, cataracts, movement disorder, endocrine dysfunction, and immunodeficiency who remained undiagnosed despite multiple negative clinical genomic diagnostic studies. Research reanalysis of PacBio long-read genome sequencing data identified compound heterozygous LIG3 variants, including a splice variant and a novel 98 bp insertion. Western blot confirmed loss of LIG3 protein expression and RNA-seq demonstrated aberrant transcripts. Muscle biopsy revealed mitochondrial dysfunction, with COX-deficient fibers and complex IV deficiency. Notably, this is the first reported association of LIG3 deficiency with immunologic and endocrine abnormalities, emphasizing the importance of a broad approach to phenotype-genotype.