Abstract
We report a neonatal patient with hypertrophic cardiomyopathy (HCM), lactic acidosis and isolated complex I deficiency. Using a customized next-generation sequencing panel, we identified a novel hemizygous variant c.338G>A in the X-linked NDUFB11 gene that encodes the NADH: ubiquinone oxidoreductase subunit B11 of the mitochondrial respiratory chain (MRC) complex I (CI). Molecular and functional assays performed in the proband’s target tissues—skeletal and heart muscle—showed biochemical disturbances of the MRC, suggesting a pathogenic role for this variant. In silico analyses initially predicted an amino acid missense change p.(Arg113Lys) in the NDUFB11 CI subunit. However, we showed that the molecular effect of the c.338G>A variant, which is located at the last nucleotide of exon 2 of the NDUFB11 gene in the canonical ‘short’ transcript (sized 462 bp), instead causes a splicing defect triggering the up-regulation of the expression of an alternative ‘long’ transcript (sized 492 bp) that can also be detected in the control individuals. Our results support the hypothesis that the canonical ‘short’ transcript is required for the proper NDUFB11 protein synthesis, which is essential for optimal CI assembly and activity, whereas the longer alternative transcript seems to represent a non-functional, unprocessed splicing intermediate. Our results highlight the importance of characterizing the molecular effect of new variants in the affected patient’s tissues to demonstrate their pathogenicity and association with the clinical phenotypes.