Diagnostic Odyssey of Atypical Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) Explained by Three...

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive mitochondrial defect of long-chain fatty acid β-oxidation, caused by biallelic pathogenic variants in HADHA or HADHB. We report a 22-year-old male with an atypically mild presentation of LCHADD who was referred to the Undiagnosed Diseases Network (UDN). Trio genome sequencing identified a maternally inherited HADHA frameshift pathogenic variant and a paternally inherited noncoding rare HADHA variant. The paternal noncoding variant was predicted by in silico splicing analysis to create a cryptic splice donor site. This was experimentally confirmed to partially perturb splicing, leading to partial disruption of normal splicing and the production of both normal and aberrant transcripts. Transcripts derived from the cryptic donor site were subject to nonsense-mediated decay (NMD). As a result, the proband's cells produced three HADHA transcripts: a truncated maternal transcript that was destroyed by NMD, an abnormally spliced paternal transcript also subject to NMD, and a normally spliced paternal transcript. The presence of residual normally spliced HADHA transcripts from the paternal allele likely contributes to partial preservation of LCHAD enzyme function and provides a plausible explanation for the proband's attenuated clinical phenotype.