Intellectual disability
Gene: NBEA

NBEA (neurobeachin)
EnsemblGeneIds (GRCh38): ENSG00000172915
EnsemblGeneIds (GRCh37): ENSG00000172915
OMIM: 604889, Gene2Phenotype
NBEA is in 5 panels

2 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team: After discussion with the Genomics England Clinical team, there is sufficient evidence has been provided by the external expert review for this gene to be rated green. NBEA is not associated with any phenotypes on OMIM and Gene2Phenotype.
Created: 18 Mar 2019, 12:06 p.m.

Created: 18 Mar 2019, 12:06 p.m.

Panel version: 2.787

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID: 30269351 is a collaborative study reporting on 24 individuals with pathogenic de novo variants affecting NBEA.

All subjects presented with neurodevelopmental disorder including developmental delay or intellectual disability. Half of the patients (12/24) had autistic features or autism.

Epilepsy was a feature in 15/24 (62.5%) of patients with onset before the age of 4 years in the majority (approx. 85%). Of the 15 patients with seizures, 80% presented with generalized seizures of variable type (myoclonic, atonic and/or myoclonic-atonic, absence, tonic, clonic or tonic-clonic), 6.67% with focal seizures only and 13.33% with unclassified seizure type.

Other features included developmental microcephaly (or borderilne microcephaly) in 3/24 individuals or developmental regression in 2/24.

Among the variants identified:
8/24 were stopgain SNVs
5/24 were frameshift
4/24 were missense SNVs
1/24 was a splice site SNV
5/24 concerned an intragenic NBEA deletion
1/24 concerned a 2.87 Mb deletion spanning NBEA as well as additional genes (none of latter associated with disease in OMIM).

Two of these individuals were reported in a previously published study of children with DD/ID (PMID: 28554332).

Individuals with developmental disorders and de novo coding mutations in NBEA have been reported in further publications including the DDD study (PMID: 28135719 - subject DDD4K.01714), most summarized in the denovo-db (http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=NBEA)

As also commented in the article, a patient with autism and a de novo balanced translocation disrupting NBEA has been reported (PMID: 12746398) as has also been the case with other deletions spanning NBEA (PMIDs: 12826745, 11450821, 3377648).

Previous studies have suggested a role for NBEA in regulation of synaptic structure and function (PMID: 23277425,22109531) as well as a role of neurobeachin in autism-like behaviors in mice (PMID: 23153818).

NBEA is intolerant to loss-of-function mutations (pLI=1 in ExAC). Most variants in the study predict loss-of-function. As a result happloinsufficiency seems to be the underlying mechanism.

As the authors propose, loss-of-function variants might be associated with more specific (eg. microcephaly or myoclonic-atonic seizures) or severe phenotypic presentations, although the size of the cohort did not not allow safe conclusions. //

NBEA is included in DD/ID (but not epilepsy) gene panels offered by different diagnostic labs. //

As a result this gene can be considered for inclusion as green in the intellectual disability and epilepsy panels.
Created: 16 Oct 2018, 10:42 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Seizures

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 16 Oct 2018, 10:42 a.m.

Panel version: 2.510

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green

Phenotypes

Global developmental delay
Intellectual disability
Seizures
No OMIM number

OMIM

604889

Clinvar variants

Variants in NBEA

Penetrance

unknown

Publications

Panels with this gene