Aberrant pseudoexon inclusion is rarely recognised as a cause of human disease. Here we report two novel, compound heterozygous mutations in nicotinamide nucleotide transhydrogenase (NNT), one of which activates a pseudoexon, as the cause of familial glucocorticoid deficiency in two siblings. Whole-exome sequencing identified a single novel, heterozygous variant (R71X) in both affected individuals. Follow-up cDNA analysis identified the pseudoexon inclusion (p.P998_D999ins23) and Sanger sequencing of genomic DNA identified a 4 bp duplication responsible for its activation. The variants segregated with the disease, R71X was inherited from the mother, P998_D999ins23 from the father and an unaffected sibling had inherited only the R71X variant. Neither variant has been annotated in any SNP or mutation databases and both will lead to premature truncation and presumably an inactive protein. The mutation resulting in pseudoexon inclusion could provide a potential target for antisense oligonucleotide therapy. Detection of such events in disease is hampered since introns, because of their frequently large size, are often excluded from mutational analyses, and it is often impossible/impractical to perform cDNA analysis.
12 - 14 Nov 2014
British Society for Paediatric Endocrinology and Diabetes