Bachmann-Gagescu Ruxandra, Phelps Ian G, Dempsey Jennifer C, Sharma Vivek A, Ishak Gisele E, Boyle Evan A, Wilson Meredith, Marques Lourenço Charles, Arslan Mutluay, Shendure Jay, Doherty Dan
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Hum Mutat. 2015 Sep;36(9):831-5. doi: 10.1002/humu.22821. Epub 2015 Jul 2.
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum.
乔伯特综合征（JS）是一种隐性神经发育障碍，其特征为独特的中后脑畸形。基于其重叠的表型以及与原发性纤毛功能障碍相关的共同潜在病理生理学，JS属于一组称为纤毛病的疾病。28个基因中的任何一个发生双等位基因突变，所有这些基因都编码定位于原发性纤毛或基体的蛋白质，都可导致JS。尽管有这么多基因，但目前约62%的JS患者能够确定其遗传病因。为了鉴定新的JS基因，我们对35名JS患者进行了全外显子组测序，在一名患者中发现KIAA0586基因存在双等位基因罕见有害变异（RDV），该基因编码纤毛发生所需的一种中心体蛋白。在一个大型JS队列中进行的靶向二代测序在另外8个家系中发现了双等位基因RDV，估计患病率为2.5%（9/366个JS家系）。所有受影响个体的JS表型都处于该谱系的轻度范围。
