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The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in  EXOSC5 , which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of  EXOSC5  were studied in detail. The first patient had a deletion involving exons 5–6 of  EXOSC5  and a missense variant, p.Thr114Ile, that were inherited  in trans , the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in  EXOSC5  and the p.Thr114Ile missense variant that were inherited  in trans . We employed three complementary approaches to explore the requirement for  EXOSC5  in brain development and assess consequences of pathogenic  EXOSC5  variants. Loss of function for  exosc5  in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic  EXOSC5  variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness