Submission Details

The relationship between NBEA variants and neurodevelopmental disorders was first suggested after Castermans et al. reported a male patient with isolated autism and a de novo translocation t(5;13)(q12.1;q13.2) (PMID: 12746398). The breakpoint on 13q falls within the second intron of the NBEA gene and is expected to disrupt its expression. Though this case was not scored, this case ultimately led to further investigation of this gene as a potential cause for neurodevelopmental disorders. To date more than 20 de novo NBEA variants have been reported in patients with neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorder, and epilepsy (PMID: 30269351, 25363768, 25363760, 31452935). Most of the reported variants are de novo loss-of-function variants, including nonsense, frameshift, and splice site variants, as well as intragenic deletions; some missense variants have also been reported. This gene is intolerant to both loss-of function and missense variants, as indicated by its pLI score of 1 and missense Z score of 5.51 in the gnomAD database (v2.1.1). This gene-disease relationship is further supported by Drosophila, zebrafish, and mouse models as well as rescue experiments (PMID: 26100104, 25484298, 15071111, 23153818, 23100440). In summary, NBEA is definitively associated with complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/2/2020.