Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL) to neurodevelopmental disorder and cerebellar atrophy… Click to show full abstract
Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL) to neurodevelopmental disorder and cerebellar atrophy with or without seizures (NEDCAS), without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at BRAT1 locus. Two siblings displayed non-progressive congenital ataxia and shrunken cerebellum on MRI. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hiterto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skipping. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of non-progressive cerebellar signs, even without a neurodevelopmental disorder. This article is protected by copyright. All rights reserved.
               
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