Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

Abstract

The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remains unclear. We performed a systematic secondary-variant burden analysis of two independent Bardet-Biedl syndrome (BBS) cohorts with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants compared to either population controls or to a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes, a finding corroborated by the observation of epistatic interactions involving this complex in vivo.These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model paradigm for secondary-variant burden analysis in recessive disorders.A persistent hurdle in interrogating the role of genetic background in human genetic disorders is our limited understanding of the properties and distribution of contributory alleles. The challenge is particularly acute in rare disorders, in which the allele frequency of both causal variants and secondary contributory alleles (i.e. alleles in loci other than the primary locus) is often low; as such population-based studies are hampered by the lack of statistical power. At the same time, transitioning from a single-gene-centric to a systems-based disease architecture defined by biological modules can inform causality, penetrance and expressivity 1 . Bardet-Biedl syndrome, a model ciliopathy, represents an opportunity to study secondary-variant burden. We and others have shown previously that BBS patients can carry secondary pathogenic variants in known BBS genes 2 . In rare examples, such alleles can modify penetrance 3 , whereas, more commonly, they are thought to modulate expressivity 4,5 . However, initial population-based studies have failed to detect an enrichment for secondary alleles in trans (i.e. alleles in loci other than the primary locus), suggesting that either some of the examples were exceptions, or that the incidence, distribution, and frequency of such alleles might be different than assumed a priori 6 . Here, we studied two BBS cohorts with unambiguous recessive pathogenic mutations in 17 established BBS genes to measure a) whether there is enrichment for secondary variants beyond the driver locus; and b) if so, whether the excess variation is concentrated within discrete disease modules or whether it is randomly distributed.

A case of Bardet‑Biedl syndrome caused by a recurrent variant inBBS12: A case report

“…The underlying molecular mechanism is often complicated through the intervention of a third mutant locus, giving rise to ‘triallelic inheritance’, which may explain the extensive clinical variability of patients with BBS ( 50 ). Similarly, it has been hypothesized that the presence of second-site modifier or epistatic interactions are responsible both for intrafamilial or interfamilial clinical heterogeneity and for the severity of the phenotype ( 2 , 51 , 52 ). Copy number variants and retrotransposon insertions have been proposed to contribute to the pathogenesis of BBS ( 53 , 54 ).…”

Bardet–Biedl Syndrome—Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype–Phenotype Correlations

“…Moreover, 12 additive interaction effects were found between the main complexes (BBSome, chaperonin and transition zone) and 1 between proteins of transition zone and others gene BBS1-BBS5, BBS1-BBS2, BBS1-NPHP1, BBS10-NPHP1, BBS2-NPHP1, BBS9-NPHP1, BBS7-NPHP1, BBS2-BBS4, BBS2-MKKS, BBS4-MKKS, BBS4-BBS9, BBS4-BBS7. On the other hand, no interaction effect was demonstrated in the following genes (nor additive or epistatic effect): TRIM32, WDPCP, CEP290, MKS1 [71].…”

Update of genetic variants in CEP120 and CC2D2A—With an emphasis on genotype‐phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies

“…Interestingly, a minority of patients with MKS/ML presented with biallelic missense changes in CC2D2A and a homozygous missense variant p.(Pro1122Ser) in CC2D2A was detected in patients with JBTS and MKS, suggesting additional phenotype modifying factors are at work, such as trans-acting genetic modifiers. Along these lines, a recent study established enrichment for secondary variants beyond the driver locus in cohorts of recessive ciliopathy patients (Bardet-Biedl syndrome) that might potentially contribute to disease expressivity (Kousi et al, 2020). Large-scale human sequencing projects suggest major differences in pre-mRNA splicing and basal exon skipping between different organs for most of our transcriptome.…”