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Early onset or syndromic epilepsy v1.331 NBEA Rebecca Foulger Source Wessex and West Midlands GLH was added to NBEA.
Early onset or syndromic epilepsy v1.330 NBEA Rebecca Foulger Source NHS GMS was added to NBEA.
Early onset or syndromic epilepsy v1.316 NBEA Rebecca Foulger commented on gene: NBEA: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.262 NBEA Rebecca Foulger reviewed gene: NBEA: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.261 NBEA Helen Lord reviewed gene: NBEA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.34 NBEA Ivone Leong Classified gene: NBEA as Green List (high evidence)
Early onset or syndromic epilepsy v1.34 NBEA Ivone Leong Gene: nbea has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.33 NBEA Ivone Leong gene: NBEA was added
gene: NBEA was added to Genetic epilepsy syndromes. Sources: Expert list
Mode of inheritance for gene: NBEA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NBEA were set to 30269351; 28554332; 12746398; 12826745; 11450821; 3377648; 23277425; 22109531; 23153818
Phenotypes for gene: NBEA were set to Global developmental delay; Intellectual disability; Seizures; No OMIM number
Review for gene: NBEA was set to GREEN
Added comment: 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
Early onset or syndromic epilepsy v0.503 NBEA Konstantinos Varvagiannis gene: NBEA was added
gene: NBEA was added to Genetic Epilepsy Syndromes. Sources: Expert Review,Literature
Mode of inheritance for gene: NBEA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NBEA were set to 30269351; 28554332; 12746398; 12826745; 11450821; 3377648; 23277425; 22109531; 23153818
Phenotypes for gene: NBEA were set to Global developmental delay; Intellectual disability; Seizures
Penetrance for gene: NBEA were set to unknown
Review for gene: NBEA was set to GREEN
Added comment: 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 Review, Literature