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

被引:5
作者
Qi, Yiming [1 ,2 ]
Ji, Xueqi [1 ,3 ]
Ding, Hongke [1 ,2 ]
Liu, Ling [1 ,2 ]
Zhang, Yan [1 ,2 ]
Yin, Aihua [1 ,2 ,3 ]
机构
[1] Guangdong Women & Children Hosp, Prenatal Diag Ctr, Guangzhou, Peoples R China
[2] Guangdong Women & Children Hosp, Maternal & Children Metab Genet Key Lab, Guangzhou, Peoples R China
[3] Guangzhou Med Univ, Clin Med Coll, Guangzhou, Peoples R China
关键词
BRAT1; nonprogressive cerebellar ataxia syndrome; synonymous variant; intron retention; prenatal diagnosis; MULTIFOCAL SEIZURE SYNDROME; LETHAL NEONATAL RIGIDITY; ENCEPHALOPATHY; MUTATIONS; PATIENT; FAMILY; MODEL;
D O I
10.3389/fgene.2022.821587
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
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页数:12
相关论文
共 33 条
[1]   Detained introns are a novel, widespread class of post-transcriptionally spliced introns [J].
Boutz, Paul L. ;
Bhutkar, Arjun ;
Sharp, Phillip A. .
GENES & DEVELOPMENT, 2015, 29 (01) :63-80
[2]  
Celik Y, 2017, EPILEPSY BEHAV CASE, V8, P31, DOI 10.1016/j.ebcr.2017.05.003
[3]   CIDE domains form functionally important higher-order assemblies for DNA fragmentation [J].
Choi, Jae Young ;
Qiao, Qi ;
Hong, Se-Hoon ;
Kim, Chang Min ;
Jeong, Jae-Hee ;
Kim, Yeon-Gil ;
Jung, Yong-Keun ;
Wu, Hao ;
Park, Hyun Ho .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2017, 114 (28) :7361-7366
[4]   An intronic variant inBRAT1creates a cryptic splice site, causing epileptic encephalopathy without prominent rigidity [J].
Colak, Fatma Kurt ;
Guleray, Naz ;
Azapagasi, Ebru ;
Yazici, Mutlu Uysal ;
Aksoy, Erhan ;
Ceylan, Nesrin .
ACTA NEUROLOGICA BELGICA, 2020, 120 (06) :1425-1432
[5]   Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus [J].
Dudding, TE ;
Friend, K ;
Schofield, PW ;
Lee, S ;
Wilkinson, IA ;
Richards, RI .
NEUROLOGY, 2004, 63 (12) :2288-2292
[6]  
Fernandez-Jaen A., 2016, NEUROONCOL OPEN ACCE, V1, P1
[7]   Mutations in BRAT1 cause autosomal recessive progressive encephalopathy: Report of a Spanish patient [J].
Fernandez-Jaen, Alberto ;
Alvarez, Sara ;
So, Eui Young ;
Ouchi, Toru ;
Jimenez de la Pena, Mar ;
Duat, Anna ;
Martin Fernandez-Mayoralas, Daniel ;
Laura Fernandez-Perrone, Ana ;
Albert, Jacobo ;
Calleja-Perez, Beatriz .
EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY, 2016, 20 (03) :421-425
[8]   Lethal Neonatal Rigidity and Multifocal Seizure Syndrome-A Misnamed Disorder? [J].
Hanes, Ilana ;
Kozenko, Mariya ;
Callen, David J. A. .
PEDIATRIC NEUROLOGY, 2015, 53 (06) :535-540
[9]   BRAT1 Mutations Are Associated with Infantile Epileptic Encephalopathy, Mitochondrial Dysfunction, and Survival Into Childhood [J].
Horn, Denise ;
Weschke, Bernhard ;
Knierim, Ellen ;
Fischer-Zirnsak, Bjoern ;
Stenzel, Werner ;
Schuelke, Markus ;
Zemojtel, Tomasz .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2016, 170 (09) :2274-2281
[10]   A Higher Mutational Burden in Females Supports a "Female Protective Model" in Neurodevelopmental Disorders [J].
Jacquemont, Sebastien ;
Coe, Bradley P. ;
Hersch, Micha ;
Duyzend, Michael H. ;
Krumm, Niklas ;
Bergmann, Sven ;
Beckmann, Jacques S. ;
Rosenfeld, Jill A. ;
Eichler, Evan E. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2014, 94 (03) :415-425