BRAT1 – Neurodevelopmental Disorder with Cerebellar Atrophy and with or without Seizures

Biallelic pathogenic variants in BRAT1 cause an autosomal recessive neurodevelopmental disorder characterized by cerebellar atrophy with or without seizures (NEDCAS). A recent systematic review collated data from 50 patients, highlighting a broad phenotypic spectrum from early-infantile onset to survival into adulthood (PMID:38607605).

The inheritance pattern is autosomal recessive. To date, over 50 probands harbor biallelic BRAT1 variants, including missense, frameshift, canonical splice-site and deep intronic changes (PMID:38607605). The variant spectrum comprises at least 39 unique nucleotide changes, with recurrent frameshift alleles such as c.638_639insA (p.Val214fs), and deep intronic c.128-1585>G causing cryptic exon inclusion (PMID:39586739).

Segregation in multiple consanguineous and non-consanguineous families confirms pathogenicity. For example, three affected siblings homozygous for c.128-1585>G (p.Thr465=) demonstrate variable penetrance of nystagmus and ataxia (HP:0000639, HP:0001251) into their twenties (PMID:39586739). Two siblings with compound heterozygous c.176T>C (p.Leu59Pro) and c.962_963del (p.Leu321ProfsTer81) presented with Ohtahara syndrome and hypertonia, dying in infancy (PMID:25319849). Additional affected sib-pairs in NPCA studies further support segregation (PMID:31742228).

Functional studies reveal multiple pathogenic mechanisms. Deep intronic and splice-site variants alter BRAT1 transcript processing in patient-derived cells (PMID:39586739). BRAT1 interacts with the Integrator complex (INTS9/INTS11); loss of BRAT1 disrupts UsnRNA and histone pre-mRNA 3′ end processing in cellular models and impairs neuronal differentiation in mESCs, reversible by wild-type but not mutant BRAT1 (PMID:36028512). Western blotting and mitochondrial assays in NPCA cell lines demonstrate decreased BRAT1 protein without ATM or PDH defects (PMID:31742228).

Attenuated phenotypes include nonprogressive cerebellar ataxia and survival into late childhood, underscoring phenotypic heterogeneity (PMID:31742228, PMID:38607605). No studies have robustly refuted the association. Overall, the genetic and functional concordance supports a strong gene–disease relationship.

Key Take-home: BRAT1 genetic testing enables accurate diagnosis of NEDCAS, guides prognosis, and informs reproductive counseling.

References

• Clinical genetics • 2025 • Novel BRAT1 Deep Intronic Variant Affects Splicing Regulatory Elements Causing Cerebellar Hypoplasia Syndrome: Genotypic and Phenotypic Expansion. PMID:39586739
• Acta neurologica Belgica • 2024 • Clinical characteristics of BRAT1-related disease: a systematic literature review. PMID:38607605
• Journal of human genetics • 2014 • Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly. PMID:25319849
• Nature communications • 2022 • BRAT1 links Integrator and defective RNA processing with neurodegeneration. PMID:36028512
• Neurology. Genetics • 2019 • Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia. PMID:31742228

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