Discovery of genotype–phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RIC1 is associated with musculoskeletal and dental conditions. Whole-exome sequencing identified individuals homozygous-by-descent for a rare variant in RIC1 and, through a guided clinical re-evaluation, it was discovered that they share signs with the BioVU-associated phenome. We named this new Mendelian syndrome CATIFA (cleft lip, cataract, tooth abnormality, intellectual disability, facial dysmorphism, attention-deficit hyperactivity disorder) and revealed further disease mechanisms. This gene-based, PheWAS-guided approach can accelerate the discovery of clinically relevant disease phenome and associated biological mechanisms.

基因型-表型关系的发现仍然是临床医学的主要挑战。在这里，我们结合了三个表型数据来源，揭示了胶原蛋白分泌不足导致的罕见和常见疾病的新机制。使用斑马鱼遗传筛选，我们确定ric1基因对骨骼生物学至关重要。在 EHR 关联的 BioVU 生物库中使用基于基因的全表型关联研究 (PheWAS)，我们表明RIC1基因决定的表达减少与肌肉骨骼和牙齿状况有关。全外显子组测序鉴定了RIC1罕见变异的纯合子血统个体并且，通过指导性临床重新评估，发现它们与 BioVU 相关表型具有相同的迹象。我们将这种新的孟德尔综合征命名为 CATIFA（唇裂、白内障、牙齿异常、智力障碍、面部畸形、注意力缺陷多动障碍），并揭示了进一步的疾病机制。这种基于基因、PheWAS 指导的方法可以加速发现临床相关疾病表型和相关生物学机制。