Biallelic protein truncating EXOSC6 variants cause a neurodevelopmental disorder with cerebellar atrophy, ataxia, and...

The multisubunit RNA exosome complex provides an essential, highly conserved multifunctional 3' to 5' exoribonuclease activity in the eukaryotic nucleus and cytoplasm. Inherited bi-allelic single amino acid variants in the core of the RNA exosome complex have been implicated in causing Mendelian syndromes that affect brain development, collectively termed exosomopathies. The core RNA exosome consists of nine subunits, and pathogenic variants in eight of them (EXOSC1- 5 and EXOSC7-9) have been described in exosomopathies. Here, we describe a patient with cerebellar atrophy, ataxia, and global developmental delay. Trio exome sequencing identified compound heterozygous variants in the final subunit EXOSC6. Previous patients with exosomopathies all have an RNA exosome with only a single amino acid changed, but our patient is missing multiple amino acid residues. The maternal allele is an in-frame deletion that removes 4 amino acids, while the paternal allele introduces a stop codon that removes the last 16 amino acids of EXOSC6. Functional analyses of the variants in a yeast model suggest that both variants are damaging and may affect protein stability. The paternal variant affects a C-terminal α-helix. We tested several other alleles in this helix in our yeast model and show it is important. Overall, our findings broaden the variants implicated in exosomopathies.