Biallelic protein truncating EXOSC6 variants cause a neurodevelopmental disorder with cerebellar atrophy, ataxia, and global developmental delay

Biallelic loss of function of an RNA exosome core subunit: an in-frame deletion and a C-terminal truncation of EXOSC6 destabilise the protein and impair the 3' exoribonuclease activity of the complex.

The RNA exosome complex provides an essential, highly conserved 3' exoribonuclease activity in the nucleus and cytoplasm of eukaryotic cells, and biallelic variants in its core cause a group of Mendelian syndromes affecting brain development, collectively termed exosomopathies. Of the nine core subunits, eight had already been implicated — EXOSC1 to EXOSC5 and EXOSC7 to EXOSC9 — and this work describes the ninth and final one, EXOSC6, in a patient with cerebellar atrophy, ataxia and global developmental delay. Trio exome sequencing identified compound heterozygous variants: the maternal allele is an in-frame deletion removing four amino acids, while the paternal allele introduces a premature stop codon that removes the last sixteen amino acids of the protein, including a C-terminal alpha helix. Unlike all previously published exosomopathy patients, in whom a single amino acid was altered, this patient is missing several residues. Functional analyses in a yeast model indicate that both variants are damaging and likely affect protein stability, and testing further alleles across that same helix confirms its importance.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The contribution here is not adding a gene to a panel — EXOSC6 is already captured by any exome — but making a class of variants interpretable that until now came back as VUS: the exosomopathy family is complete, and cerebellar atrophy with ataxia in a patient carrying two EXOSC6 variants can be tied to an established mechanism. Two caveats weigh heavily: this is a single patient with no segregation in other families, and yeast remains a distant system for a human neurodevelopmental phenotype. It is also a preprint that has not been peer reviewed, which should rule out any formal reclassification until publication and further independent cases.

Analysis by Dr Thibaut Benquey