RNA sequencing identifies a cryptic exon caused by a deep intronic variant in NDUFB10 resulting in isolated Complex I deficiency.

Abstract

The diagnosis of mitochondrial disorders remains a challenging and often unmet need. We sought to investigate a sibling pair with suspected mitochondrial disease and a clinical presentation notable for global developmental delay, poor growth, sensorineural hearing loss, and brain MRI abnormalities, both with early death. Following uninformative exome and genome sequencing of the family quartet, RNA sequencing was pursued as an orthogonal testing strategy. RNA sequencing of fibroblasts from the older sibling identified the presence of a cryptic exon in intron 1 of NDUFB10, that included an in-frame stop codon. NDUFB10 encodes a subunit of mitochondrial OXPHOS complex I. Differential expressio..