NBEA

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0030930

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030930

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0030930

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Illumina

The NBEA gene is located on chromosome 13 at 13q13.3 and encodes the neurobeachin protein. Neurobeachin is an A-kinase anchor protein and thus functions in the anchoring or targeting of protein kinase A. It is highly expressed in the brain, and studies have suggested it may play a role in membrane trafficking in neurons. NBEA was first reported in relation to autosomal dominant NBEA-related intellectual disability in 2018 (30269351: Mulhern et al. 2018). At least eight unique variants, primarily null variants, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in eight probands from a single publication (30269351: Mulhern et al. 2018). In the majority of cases, the variant occurred de novo. While the maximum score for genetic evidence (12 pts.) has been reached, additional independent reports are needed to replicate the association. The mechanism of disease appears to involve haploinsufficiency. This gene-disease association is supported by expression data and the observation of reduced synaptic current amplitudes in cultured neurons from knock-out mice (11102458: Wang et al. 2000; 23277425: Nair et al. 2013). In summary, there is strong evidence to support this gene-disease relationship.