Novel Biallelic Loss-of-Function Variants in CEP290 Cause Joubert Syndrome in Two Siblings

Abstract BackgroundJoubert Syndrome (JS) is a rare genetic disorder, which can be defined by brainstem malformation, cerebellar vermis hypoplasia and consequent “molar tooth sign” (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here we investigated a JS case in two male siblings aged 4 and 10 years old and uncovered a novel pathogenesis through combined methods.Results The siblings shared similar features of nystagmus, delayed intellectual development. typical MTS, and abnormal morphology in fourth ventricle. Whole exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense mutation (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exon 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: qPCR, and PCR-sequencing.Conclusions In this study, we first reported a novel causative mechanism of Joubert Syndrome: a copy number variation (CNV) compounding with a point mutation in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.