Clinical variability at the mild end of BRAT1‐related spectrum: Evidence from two families with genotype–phenotype discordance

Claudio Sette, Sara Nuovo, Valentina Baglioni, Roberta De Mori, Silvia Tardivo, Caterina Caputi, Monia Ginevrino, Alessia Micalizzi, Laura Masuelli, Giulia Federici, Antonella Casella, Elisa Lorefice, Danila Anello, Manuela Tolve, Donatella Farini, Enrico Bertini, Ginevra Zanni, Lorena Travaglini, Gessica Vasco, Carla CarducciEnza M. Valente, Vincenzo Leuzzi

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

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 to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, 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 the BRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. 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 hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. 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 nonprogressive cerebellar signs, even without a neurodevelopmental disorder.
Lingua originaleEnglish
pagine (da-a)1-7
Numero di pagine7
RivistaHuman Mutation
Volume2021
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • BRAT1
  • NEDCAS
  • nonprogressive congenital ataxia
  • phenotypic discordance
  • splicing variant.

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