Ben-Omran Tawfeg, Fahiminiya Somayyeh, Sorfazlian Natalie, Almuriekhi Mariam, Nawaz Zafar, Nadaf Javad, Khadija Kitam Abu, Zaineddin Samiha, Kamel Hussein, Majewski Jacek, Tropepe Vincent
Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Weill-Cornell Medical College, Doha, Qatar.
Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
J Med Genet. 2015 Jun;52(6):381-90. doi: 10.1136/jmedgenet-2014-102707. Epub 2015 Apr 14.
Neuroanatomical defects are often present in children with severe developmental delay and intellectual disabilities. Few genetic loci have been associated with disorders of neurodevelopment. Our objective of the present study was to analyse a consanguineous Arab family showing some of the hallmark signs of a rare cerebellar hypoplasia-related neurodevelopmental syndrome as a strategy for discovering a causative genetic mutation.
We used whole exome sequencing to identify the causative mutation in two female siblings of a consanguineous Arab family showing some of the hallmark signs of a cerebellar-hypoplasia-related neurodevelopmental disorder. Direct Sanger sequencing was used to validate the candidate mutations that cosegregated with the phenotype. Gene expression and loss of function studies were carried out in the zebrafish model system to examine the role of the candidate gene in neurodevelopment.
Patients presented with severe global developmental delay, intellectual disability, hypoplasia of the cerebellum and biochemical findings suggestive of nephrotic disease. Whole exome sequencing of the two patients revealed a shared nonsense homozygous variant in WDR73 (p.Q235X (c.703C>T)) resulting in loss of the last 144 amino acids of the protein. The variant segregated according to a recessive mode of inheritance in this family and was absent from public and our inhouse databases. We examined the developmental role of WDR73 using a loss-of-function paradigm in zebrafish. There was a significant brain growth and morphogenesis defect in wdr73 knockdown embryos resulting in a poorly differentiated midbrain and cerebellum.
The results provide new insight into the functional role of WDR73 in brain development and show that perturbation of its function in an inherited disorder in humans is associated with cerebellar hypoplasia as well as nephrotic disease, consistent with Galloway-Mowat Syndrome.
神经解剖学缺陷在患有严重发育迟缓及智力残疾的儿童中常常存在。很少有基因位点与神经发育障碍相关。本研究的目的是分析一个近亲阿拉伯家庭，该家庭呈现出一种罕见的与小脑发育不全相关的神经发育综合征的一些标志性体征，以此作为发现致病基因突变的策略。
我们使用全外显子组测序来鉴定一个近亲阿拉伯家庭中两名女性同胞的致病突变，该家庭呈现出与小脑发育不全相关的神经发育障碍的一些标志性体征。使用直接桑格测序法验证与表型共分离的候选突变。在斑马鱼模型系统中进行基因表达和功能丧失研究，以检查候选基因在神经发育中的作用。
患者表现为严重的全面发育迟缓、智力残疾、小脑发育不全以及提示肾病的生化检查结果。对两名患者进行全外显子组测序发现，WDR73基因存在一个共同的纯合无义变异（p.Q235X (c.703C>T)），导致该蛋白最后144个氨基酸缺失。该变异在这个家族中按照隐性遗传模式分离，并且在公共数据库和我们的内部数据库中均未出现。我们在斑马鱼中使用功能丧失模式研究了WDR73的发育作用。wdr73基因敲低的胚胎出现了明显的脑生长和形态发生缺陷，导致中脑和小脑分化不良。
这些结果为WDR73在脑发育中的功能作用提供了新的见解，并表明在人类遗传性疾病中其功能的扰动与小脑发育不全以及肾病有关，这与加洛韦 - 莫瓦特综合征一致。
