Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings

Xiang Wang,Hongqian Liu,Xueguang Zhang,Ying Shen,Zhu Zhang

doi:10.1186/s40246-020-00274-4

Abstract

BackgroundJoubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem 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 two male siblings with JS and uncovered a novel pathogenesis through combined methods.ResultsThe siblings shared similar features of nystagmus, disorders of 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 variant (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exons 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: quantitative PCR and PCR sequencing.ConclusionsIn this study, we first reported a novel causative mechanism of Joubert syndrome: a copy number variation (CNV) combined with a single-nucleotide variant in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.

Highlights

Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent “molar tooth sign” (MTS)
Only one research reported a deletion from intron 43 of CEP290 to C12orf29 [20]; there were no other copy number variation (CNV) in CEP290 were reported in JS patients yet
The nature of JS associated with CEP290 is an autosomal recessive inheritance, so we considered that there should be another variant in CEP290

Summary

Introduction

Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent “molar tooth sign” (MTS). With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. As with other genes associated with JS, CEP290 is a primary cilium-related gene encoding centrosomal protein 290, a large essential protein expressed in almost all tissues and playing a critical role in cell motility and division through effects on centrosome and cilia development [11,12,13]. Dozens of variants in CEP290 have been identified to cause JBTS5 (OMIM#610188) [16], a subtype of JS mainly associated with serve retinal and renal involvement in affected individuals [17]. Only one research reported a deletion from intron 43 of CEP290 to C12orf (chromosome 12 open reading frame 19) [20]; there were no other CNVs in CEP290 were reported in JS patients yet

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