Compound heterozygosity of EXOSC2 ‘missense’ variants causes a bi-allelic decrease in protein expression through novel unexpected pathomechanisms

Abstract EXOSC2 encodes one of the 11 components of the RNA exosome complex degrading various types of RNA. Pathogenic variants of some EXOSC genes cause genetic disorders with similar phenotypes, including intellectual disability (ID), microcephaly, and pontocerebellar hypoplasia. However, little is known regarding EXOSC2 . We report detailed analyses of compound heterozygosity of novel EXOSC2 variants, comprising paternally-inherited c.14T > G (p.M5R) and maternally-inherited c.317C > T (p.S106L), identified in a patient with ID, epilepsy, and microcephaly. Although the two variants appeared ‘missense,’ they respectively decreased protein EXOSC2 expression through novel pathomechanisms. c.14T > G may have decreased EXOSC2 expression by impaired efficiency during translational initiation. Interestingly, other synonymous codons didn’t decrease the expression, suggesting the decreased expression depended on the nucleotide change instead of residue change. The second variant, c.317C > T, caused unexpected exon 4 skipping, leading to decreased EXOSC2 expression, although the nucleotide 317C was in the middle of exon 4. Since the exon skipping didn’t occur due to other changes in nucleotides adjacent to c.317C, only c.317C > T critically reduced the function of the exon enhancer element. Altogether, we identified two novel pathomechanisms explaining the decrease in EXOSC2 expression. These findings suggest the possibility that we may overlook such kind of variants decreasing gene expression, which could cause disorders. Additionally, the etiology of the current case is a decline of one of the 11 components of the exosome, similar to previously-reported disorders by other genes in the EXOSC family, with overlapping clinical features. Thus, these disorders may be integrated into a new disease concept termed “ RNA exosomepathy .”