BRAT1 mutations present with a spectrum of clinical severity.
Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, are associated with a severe phenotype known as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL; OMIM # 614498), characterized by intractable seizures, hypertonia, autonomic instability, and early death. We expand the phenotypic spectrum of BRAT1 related disorders by reporting on four individuals with various BRAT1 mutations resulting in clinical severity that is either mild or moderate compared to the severe phenotype seen in RMFSL. Representing mild severity are three individuals (Patients 1-3), who are girls (including two sisters, Patients 1-2) between 4 and 10 years old, with subtle dysmorphisms, intellectual disability, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; additionally, Patient 3 has well-controlled epilepsy and microcephaly. Representing moderate severity is a 15-month-old boy (Patient 4) with severe global developmental delay, refractory epilepsy, microcephaly, spasticity, hyperkinetic movements, dysautonomia, and chronic lung disease. In contrast to RMFSL, his seizure onset occurred later at 4 months of age, and he is still alive. All four of the individuals have compound heterozygous BRAT1 mutations discovered via whole exome sequencing: c.638dupA (p.Val214Glyfs*189); c.803+1G>C (splice site mutation) in Patients 1-2; c.638dupA (p.Val214Glyfs*189); c.419T>C (p.Leu140Pro) in Patient 3; and c.171delG (p.Glu57Aspfs*7); c.419T>C (p.Leu140Pro) in Patient 4. Only the c.638dupA (p.Val214Glyfs*189) mutation has been previously reported in association with RMFSL. These patients illustrate that, compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later-onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy. © 2016 Wiley Periodicals, Inc.
Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland.|Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland.|Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland.
Siddharth
S
Srivastava
Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Heather E
HE
Olson
Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland.
Julie S
JS
Cohen
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Cynthia S
CS
Gubbels
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Sharyn
S
Lincoln
Ambry Genetics, 15 Argonaut, Aliso Viejo, California.
Brigette Tippin
BT
Davis
Ambry Genetics, 15 Argonaut, Aliso Viejo, California.
Layla
L
Shahmirzadi
Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland.
Siddharth
S
Gupta
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Jonathan
J
Picker
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Timothy W
TW
Yu
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Claritas Genomics, Cambridge, Massachusetts.
David T
DT
Miller
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Janet S
JS
Soul
Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital, Baltimore, Maryland.
Andrea
A
Poretti
Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland.|Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland.|Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland.
SakkuBai
S
Naidu
D001921:Brain / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics; D059472:Exome; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012720:Severity of Illness Index
C573230:BRAT1 protein, human; D009687:Nuclear Proteins
BRAT1; RMFSL; cerebellar atrophy; clinical severity; epilepsy; intellectual disability