BRAT1

Inheritance Pattern: AR

Disease ID:MONDO:0013784

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013784

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0020841

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0020841

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013784

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013784

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0020841

Submitter: ClinGen

Pathogenic variants in the BRAT1 gene have been reported in the literature in several individuals with a broad spectrum of disease with features including epilepsy, developmental delay, hypertonia, microcephaly, spasticity and dysmorphic features. One form of this phenotype associated with BRAT1 has been reported in the literature as neurodevelopmental disorder with cerebellar atrophy and with or without seizures. Another form associated with more severe phenotypes (BRAT1/Neonatal-onset encephalopathy with rigidity and seizures) has been assessed separately. Compared to an earlier onset more severe presentation usually within the first days of life (documented in the literature as rigidity and multifocal seizure syndrome, lethal neonatal- RMFSL), for this phenotype, onset of symptoms is variable, usually around infancy and more attenuated. Clinical presentation is also variable with most individuals reported with developmental delay, microcephaly, hypertonia or hypotonia; of note, seizures have been reported in some but not all individuals with features of disease. Loss of function variants have been commonly reported in association with disease, however missense and inframe deletions also been reported in the literature (PMIDs: 26483087, 26494257, 31742228, 25131622, 29997391, 27282546). Supporting experimental data has demonstrated that variants in this gene result in the inability for the protein to localize to the nucleus and may affect the stability of the protein (PMIDs: 22279524, 31742228). At the time of this review, no difference in variant type has been noted between the phenotypes of this gene. In addition, the same variant has been identified in both the severe and attenuated forms of this disease. In all instances the identified variants were either homozygous or compound heterozygous supporting an autosomal recessive inheritance pattern. BRAT1 is definitively associated with neurodevelopmental disorder with cerebellar atrophy and with or without seizures. This has been demonstrated in the clinical and research settings and this evidence has been maintained over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 4/19/22 (SOP version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0013784

Submitter: ClinGen

Pathogenic variants in the BRAT1 gene have been reported in the literature in several individuals with a broad spectrum of disease with features including epilepsy, developmental delay, hypertonia, microcephaly, spasticity and dysmorphic features. A severe form of this phenotype associated with BRAT1 is characterized by neonatal-onset encephalopathy with rigidity and seizures (also reported in the literature as lethal neonatal spasticity-epileptic encephalopathy syndrome). For this phenotype, onset of symptoms is very early, usually within the first days or weeks of life, has a much more severe presentation, and often results in early death. The unusual feature of increased muscle tone in the form of rigidity sets this condition apart from other early-onset developmental and epileptic encephalopathies, Another form associated with milder phenotypes (BRAT1/neurodevelopmental disorder with cerebellar atrophy with or without seizures) has been assessed separately. Loss of function variants have been commonly reported in association with disease, however missense, inframe deletions, multi exonic deletions and at least 1 silent variant (which is suspected to result in improper splicing) have also been reported in the literature (PMIDs: 22279524, 23035047, 25319849, 3168474, 33816000). Evidence supporting this gene disease pair includes experimental data as well. Supporting experimental data has demonstrated that variants in this gene result in a failure of the protein to localize to the nucleus (PMID: 22279524). At the time of this review, no difference in variant type has been noted between the phenotypes of this gene. In addition, the same variant has been identified in both the severe and attenuated forms of this disease. In all instances the identified variants were either homozygous or compound heterozygous supporting an autosomal recessive inheritance pattern. BRAT1 is definitively associated with neonatal-onset encephalopathy with rigidity and seizures. This has been demonstrated in the clinical and research settings and this evidence has been maintained over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 4/19/22 (SOP version 8).

Inheritance Pattern: AR

Disease ID:MONDO:0013784

Submitter: Orphanet