Novel Biallelic Variant in the BRAT1 Gene Caused Nonprogressive Cerebellar Ataxia Syndrome

Abstract

Recessive mutations in BRAT1 cause lethal neonatal rigidity and multifocal seizure syndrome (RMFSL), a phenotype characterized by neonatal microcephaly, hypertonia, and refractory epilepsy with premature death. Recently, attenuated disease variants have been described, suggesting that a wider clinical spectrum of BRAT1-associated neurodegeneration exists than was previously thought. Here, we reported a 10-year-old girl with severe intellectual disability, rigidity, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; two BRAT1 variants in the trans configuration [c.1014A > C (p.Pro338 = ); c.706delC (p.Leu236Cysfs*5)] were detected using whole-exome sequencing. RNA-seq confirmed significantly decreased BRAT1 transcript levels in the presence of the variant; further, it revealed an intron retention between exon 7 and exon 8 caused by the synonymous base substitute. Subsequent prenatal diagnosis for these two variants guided the parents to reproduce. We expand the phenotypic spectrum of BRAT1-associated disorders by first reporting the pathogenic synonymous variant of the BRAT1 gene, resulting in clinical severity that is mild compared to the severe phenotype seen in RMFSL. Making an accurate diagnosis and prognostic evaluation of BRAT1-associated neurodegeneration is important for reproductive consultation and disease management.

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

“…Except for pneumonia, the clinical features of the proband in this study were comparable to typical characteristics of RMFSL. Although RMFSL has been reported in different populations, to our knowledge, RMFSL is less common among the Chinese population with only four cases reported to date (Burgess et al, 2019;Li et al, 2021;Qi et al, 2022;Van Ommeren et al, 2018). In 2018, Van et al described for the first time a female newborn affected by RMFSL with homozygous BRAT1 mutation variant c.1395G>C born to non-consanguineous Chinese parents (Van Ommeren et al, 2018).…”

“…Since the BRAT1 was first reported as the causative gene of RMFSL (Puffenberger et al, 2012), 45 mutations in the BRAT1 have been reported to date according to the Human Gene Mutation Database HGMD (http://www.hgmd.org/; Professional 2022.1) and the existing literature, including 20 missense/nonsense mutations, 8 splice mutations, 9 small deletions, 5 small insertions/duplications, and 3 gross deletions mutations (Figure 5, Table 1) (Capalbo et al, 2019;Colak et al, 2020;Fernández-Jaén et al, 2016;Hanes et al, 2015;Heide et al, 2020;Li et al, 2021;Na et al, 2020;Qi et al, 2022;Scheffer et al, 2020;Szymańska et al, 2018;Wu et al, 2021). In this study, we found a sixth splice site mutation c.431-2A>G (Colak et al, 2020;Horn et al, 2016;Srivastava et al, 2014;Stödberg et al, 2020;Rudolf et al, 2020).…”

A novel non-sense variant in the OFD1 gene caused Joubert syndrome

“…RNA sequencing was performed by Aegicare, which has been described in our previous literature ( Qi et al, 2022 ). Total RNA was extracted from peripheral blood samples of one of the carriers (I-2) and two normal females using a Qiagen blood RNA extraction kit I (QIAGEN, United States) according to the manual.…”