Identification of two novel variants in NUS1 gene in two unrelated Chinese families with intellectual disorder and epilepsy

Abstract

Background Mutations in the NUS1 gene, which encodes a Nogo-B receptor (NgBR), are related to congenital disorder of glycosylation, epilepsy, and Parkinson’s disease. However, due to the limited number of cases with genotype and detailed clinical features, more cases are needed to better understand the functional and phenotypic characteristics of NUS1 variants. In this study, we reported two unrelated Chinese individuals suffering from intellectual disorder and epilepsy. Materials and methods Whole-exome sequencing (WES) was performed on the two patients to identify pathogenic variants, and copy number variation sequencing (CNV-Seq) was conducted on the patients 2. The candidate variants were subsequently validated using Sanger sequencing. Additionally, bioinformatics analyses were used to investigate the deleteriousness of the identified variants. Results WES identified two novel variants in the NUS1 gene [NM_138459.5: c.640A > T/p.K214*, c.278delC/p.L94Wfs*11] in the two unrelated individuals with myoclonus, epilepsy, and intellectual disability. These variants resulted in truncated NgBR proteins, which lost the cis-PTase domain. According to the American College of Medical Genetics and Genomics (ACMG) classification, p.K214* was evaluated as likely pathogenic and p.L94Wfs*11 was evaluated as pathogenic. CNV-Seq analysis revealed a 0.4Mb duplication of Xq27.2q27.2 in patient 2, which was considered uncertain significance. Conclusion Our findings strongly suggest that the two novel variants in NUS1 gene may be the cause of the patient's clinical characteristics, possibly due to the loss of cis-PTase activity. Furthermore, our study expanded the genotype-phenotype spectrum of the NUS1 gene.