RNA sequencing driven diagnosis expands the phenotypic spectrum of NBAS deficiency

One in 10 individuals has a rare disease, with exome and genome sequencing yielding an overall diagnostic rate of approximately 30 %. RNA sequencing can augment genome analysis and improve diagnosis. We present a young woman with global developmental delay, poor growth, distinctive facial features, osteopenia, premature ovarian insufficiency, and ocular abnormalities who had non-diagnostic genome sequencing. RNAseq performed on her skin fibroblasts showed that NBAS gene expression was significantly reduced compared with controls. Manual inspection of the binary alignment map (BAM) files revealed compound heterozygous variants in NBAS: a rare deep intronic variant NM_015909.4:c.2423 + 403G > C which creates a hypomorphic pseudoexon not seen in control samples (gnomad allele frequency (AF) 0.000006572); and a rare premature termination codon (PTC) NM_015909.4:c.4753C > T; p.Arg1585Ter (gnomad AF 0.000006572). Both variants are predicted to cause nonsense mediated decay of transcripts, as the pseudoexon contains a PTC. Biallelic variants in NBAS are associated with two major phenotypes, i.e., infantile liver failure syndrome 2 (MIM # 616483) and short stature, optic nerve atrophy, and Pelger-Huet anomaly (MIM # 614800). Our patient, the first reported with one loss of function and one splice variant resulting in an out of frame transcript in NBAS, manifested a severe phenotype compared with previously reported individuals. This case demonstrates the utility of incorporating RNAseq to generate diagnostic candidates and expands the phenotypic spectrum of NBAS deficiency.