美国范德比尔特大学医学中心Ela W. Knapik研究组发现，通过斑马鱼模型、生物库关联和临床研究来确定与RIC1相关的孟德尔综合征。相关论文2020年1月13日在线发表于国际学术期刊《自然—医学》。
他们结合了表型数据的三种来源，揭示了由胶原蛋白分泌不足引起的罕见和常见疾病的新机制。使用斑马鱼的遗传筛选，确定ric1基因是骨骼生物学必不可少的。在基于EHR的BioVU生物库中使用基于基因的全基因组关联研究（PheWAS），他们表示RIC1基因确定的表达降低与肌肉骨骼和牙齿状况相关。全外显子组测序鉴定出的个体在RIC1中罕见地变异了纯合子血统，并且通过指导的临床重新评估，发现它们与BioVU相关的表型具有共同的标志。研究将这种新的孟德尔综合症命名为CATIFA（唇裂、白内障、牙齿异常、智力残疾、面部畸形、注意缺陷多动障碍），并揭示了进一步的疾病机制。这种基于基因，PheWAS指导的方法可以加快发现与临床相关的疾病表型和相关生物学机制的速度
据介绍，基因型-表型关系的发现，仍然是临床医学中的主要挑战。
附：英文原文
Title: Phenome-based approach identifies RIC1 -linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies
Author: Gokhan Unlu, Xinzi Qi, Eric R. Gamazon, David B. Melville, Nisha Patel, Amy R. Rushing, Mais Hashem, Abdullah Al-Faifi, Rui Chen, Bingshan Li, Nancy J. Cox, Fowzan S. Alkuraya, Ela W. Knapik
Issue&Volume: 2020/01/13
Abstract: Discovery of genotypephenotype 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. Integrated use of an animal model, a biobank for common diseases and a rare Mendelian disease leads to the discovery of a new syndrome and its pathological mechanism.
DOI: 10.1038/s41591-019-0705-y
Source:https://www.nature.com/articles/s41591-019-0705-y
Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex
本期文章：《自然—医学》：Online/在线发表
