Early onset or syndromic epilepsy

Gene: NBEA

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.

Created: 9 Sep 2019, 10:28 a.m. | Last Modified: 9 Sep 2019, 10:28 a.m.

Panel Version: 1.316

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

Green List (high evidence)

No phenotype listed on OMIM. Pubmed - Mulhern et al, 2018 (30269351) - 24 de novo NBEA variants in patients with neurodevelopmental disease (22 prev unreported and 2 reported prev in the literature). 8/24 nonsense, 5/24 fs, 4/24 missense, 5/24 intragenic del, 1/24 ss and 1/24 multigene del. 15/24 had epilepsy (62.5%) most of these cases before the age of 4 years (13/15)

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

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

Green List (high evidence)

NBEA is not associated with any phenotypes in OMIM or Gene2Phenotype. However, there is sufficient evidence provided by Konstantinos Varvagiannis for this gene to be rated green.

Expert review from Konstantinos Varvagiannis: "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."
Sources: Expert list

Created: 18 Mar 2019, 12:16 p.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Seizures; No OMIM number

Publications

• 30269351
• 28554332
• 12746398
• 12826745
• 11450821
• 3377648
• 23277425
• 22109531
• 23153818