BRAT1 – Neonatal-Onset Encephalopathy with Rigidity and Seizures

BRAT1 is implicated in neonatal-onset encephalopathy with rigidity and seizures, a severe autosomal recessive disorder characterized by hypertonia, intractable seizures, and progressive microcephaly. Pathogenic biallelic BRAT1 variants have been identified in over 97 affected individuals from 57 families across multiple populations, indicating a definitive gene–disease relationship (PMID:37344571).

Inheritance is consistently autosomal recessive, with compound heterozygous and homozygous loss-of-function variants driving disease onset in the neonatal period. Initial reports described siblings with compound heterozygous BRAT1 variants c.176T>C (p.Leu59Pro) and c.962_963del (p.Leu321ProfsTer81) presenting with Ohtahara syndrome, hypertonia, and microcephaly (PMID:25319849).

The variant spectrum encompasses frameshift, nonsense, canonical splice-site, deep intronic, and missense alleles disrupting conserved domains. Notably, recurrent frameshift mutations such as c.638dupA (p.Val214GlyfsTer189) and splice acceptor variants have been reported in multiple unrelated patients, suggesting potential hotspots in BRAT1 (PMID:27282546).

Segregation analysis within at least one multiplex family confirms cosegregation of biallelic variants with phenotype (1 additional affected relative). Functional studies reveal that BRAT1 loss impairs interaction with the Integrator complex (INTS9/INTS11), disrupting RNA 3′-end processing and neuronal differentiation, consistent with neurodegeneration seen in patients (PMID:36028512).

Collectively, genetic and experimental evidence support a definitive classification of BRAT1 in neonatal-onset encephalopathy with rigidity and seizures. Early molecular diagnosis enables prognostic counseling and reproductive planning, while functional insights highlight potential therapeutic targets in RNA processing pathways.

Key Take-home: Biallelic BRAT1 loss-of-function variants cause a definitive autosomal recessive neonatal encephalopathy with rigidity and seizures, informing clinical diagnosis, genetic counseling, and future therapeutic research.

References

• Journal of Human Genetics • 2014 • Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly. PMID:25319849
• American Journal of Medical Genetics Part A • 2016 • BRAT1 mutations present with a spectrum of clinical severity. PMID:27282546
• Nature Communications • 2022 • BRAT1 links Integrator and defective RNA processing with neurodegeneration. PMID:36028512
• European Journal of Human Genetics • 2023 • BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients. PMID:37344571

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