Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by a variety of clinical features including complex renal anomalies. A number of secondary pathogenic variants have been identified in BBS-associated genes in addition to disease-causing mutations; however, whether such variants are coincidental or disease relevant has been unclear. Now, researchers show that trans-acting secondary variants are enriched in patients with BBS, and that this enrichment is non-random.
To assess the mutational burden of secondary pathogenic variants, Nicholas Katsanis and colleagues sequenced two independent cohorts of patients with BBS and known recessive pathogenic mutations in one of 17 BBS genes. In both the discovery and replication patient cohorts the researchers observed a twofold enrichment of ultra-rare secondary variants beyond the primary locus compared with either population controls or patients with recessive alleles in this gene set but a non-BBS diagnosis.
Further analyses demonstrated the variants to be distributed non-randomly: most recessive events were found in chaperonin-encoding components. Suppression of 19 gene pairs in zebrafish revealed additive or epistatic effects; of note, all six epistatic interactions involved the suppression of chaperonin genes. “These data indicate a complex genetic architecture, consistent with increased mutational load and secondary trans-acting variants that may interact in an additive or epistatic manner with the primary locus,” says Katsanis. “Moreover, such interactions likely intimate biological architecture, wherein mutations across proteins that belong to the same macromolecular complex are additive to the phenotype, whereas mutations in different complexes are more likely to exert an epistatic effect.”
Kousi, M. et al. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy. Nat. Genet. https://doi.org/10.1038/s41588-020-0707-1 (2020)
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Allison, S.J. Secondary-variant genetic burden in Bardet–Biedl syndrome. Nat Rev Nephrol (2020). https://doi.org/10.1038/s41581-020-00370-7