Compound heterozygous loss‐of‐function variants in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome

Background Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL, OMIM 614498) is a rare autosomal recessive disease characterized by the onset of rigidity and intractable seizures at or soon after birth. The BRAT1 has been identified to be the disease‐causing gene for RMFSL. This study aimed to determine the underlying pathogenic mutations of a Chinese family with RMFSL and to confirm the effect of the splice‐site mutation by reverse transcription analysis. Methods Detailed family history and clinical data were recorded, and peripheral blood samples were collected from all available family members. Whole exome sequencing (WES), Sanger sequencing, and bioinformatics analysis were performed to investigate the causative variants. The impact of the intronic variant on splicing was subsequently analyzed by RT‐PCR analysis. Results We identified two compound heterozygous variants in the BRAT1, c.431‐2A>G in intron 3 and c.1359_1361del(p.Leu454del) in exon 9 in the proband, one inherited from each parent. Furthermore, the 3′‐splice site acceptor (c.431‐2A>G) variant was found to activate a cryptic acceptor splice site, which resulted in the loss of 29 nucleotides and generation of a premature stop codon at code 180, producing a truncated BRAT1 (c.432_460del; p.Ala145Argfs*36). Conclusions This research identified two mutations in the BRAT1 of one Chinese family with RMFSL. These data can aid in developing clinical diagnoses as well as providing genetic counseling and prenatal interventions to the family. These findings also expand our knowledge of the spectrum of BRAT1 pathogenic variants in RMFSL syndrome. Trio‐based whole‐exome sequencing (WES) and Sanger sequencing identified a novel splicing mutation c.431‐2A>G and a heterozygous truncating mutation c.1359_1361del in BRAT1 in the proband. In addition, our research demonstrated the intronic mutation could lead to aberrant mRNA splicing and further contributed to a better understanding and establishment of the genotype‐phenotype correlations in RMFSL.