2. Academic Validation
  3. BRAT1 mutations present with a spectrum of clinical severity

BRAT1 mutations present with a spectrum of clinical severity

  • Am J Med Genet A. 2016 Sep;170(9):2265-73. doi: 10.1002/ajmg.a.37783.
Siddharth Srivastava 1 2 3,  Heather E Olson 4,  Julie S Cohen 1,  Cynthia S Gubbels 5 6,  Sharyn Lincoln 5,  Brigette Tippin Davis 7,  Layla Shahmirzadi 7,  Siddharth Gupta 1,  Jonathan Picker 5,  Timothy W Yu 5 6,  David T Miller 5 8,  Janet S Soul 9,  Andrea Poretti 10,  SakkuBai Naidu 1 2 3
Affiliations

Affiliations

  • 1 Hugo W. Moser Research Institute at Kennedy Krieger Institute, Baltimore, Maryland.
  • 2 Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland.
  • 3 Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland.
  • 4 Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 5 Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 6 Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 7 Ambry Genetics, 15 Argonaut, Aliso Viejo, California.
  • 8 Claritas Genomics, Cambridge, Massachusetts.
  • 9 Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 10 Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Hospital, Baltimore, Maryland.
PMID: 27282546 DOI: 10.1002/ajmg.a.37783
Abstract

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.

Keywords

BRAT1; RMFSL; cerebellar atrophy; clinical severity; epilepsy; intellectual disability.

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