The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) 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 in patients with BBS compared with either population controls or 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 for secondary-variant burden analysis in recessive disorders.

遗传背景对驱动突变的影响已得到充分证实；然而，背景与孟德尔基因座相互作用的机制仍不清楚。我们对两个独立的 Bardet-Biedl 综合征 (BBS) 患者进行了系统的次要变异负担分析，每个患者的 17 个 BBS 基因之一均具有已知的隐性双等位基因致病突变。我们观察到，与人群对照或具有非 BBS 诊断和相同基因组隐性变异的个体队列相比，BBS 患者的反式作用罕见非同义二次变异显着富集。引人注目的是，我们发现伴侣蛋白编码基因中次级等位基因的显着过度表达——这一发现通过体内涉及该复合物的上位相互作用的观察得到了证实。这些数据表明了 BBS 的复杂遗传结构，它揭示了疾病模块的生物学特性，并提出了隐性疾病次要变异负担分析的模型。