A novel pathogenic variant of BRAT1 gene causes rigidity and multifocal seizure syndrome, lethal neonatal

摘要

ABSTRACT Introduction: Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is a severe auto-somal recessive epileptic encephalopathy characterized by microcephaly, rigidity, intractable focal seizures, apnea, and bradycardia at or soon after birth. RMFSL is related to BRCA1-associated ATM activator 1 (BRAT1) gene mutations. Methods: An Iranian couple with history of infant death due to RMFSL was referred to our genetics lab for specialized genetic counseling and testing. Whole Exome Sequencing (WES) was applied. Following WES, Sanger sequencing was performed to confirm the candidate variant. Result: A novel nonsense variant (c.2041G>T, p. E681X) was identified in exon 14 of the BRAT1 gene. Based on the American College of Medical Genetics and Genomics guideline this variant was classified as a pathogenic variant. Conclusion: This research expands the spectrum of BRAT1 pathogenic variants in RMFSL syndrome and demonstrates the utility of WES in genetic diagnostic.