BRAT1-related disease--identification of a patient without early lethality.
We present a patient with neonatal onset of hypertonia and seizures identified through whole exome sequencing to have compound heterozygous variants, c.294dupA (p.Leu99fs) and c.1925C>A (p.Ala642Glu), in the BRCA1-associated protein required for ATM activation-1 (BRAT1) gene. Variants in BRAT1 have been identified to cause lethal neonatal rigidity and multifocal seizure syndrome (OMIM# 614498), which consistently manifests a severe neurological phenotype that includes neonatal presentation of rigidity and hypertonia, microcephaly and arrested head growth, intractable seizures, absence of developmental progress, apneic episodes, and death usually by 6 months of age. Our patient initially had a similarly severe neurological picture but remains alive at 6 years of age, expanding the phenotype to include longer term survival and providing further insights into genotype-phenotype correlations and the natural history of this disease.
Department of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California.|Natera Inc., San Carlos, California.
Sheraden A
SA
Mundy
Department of Pathology, University of Utah, Salt Lake City, Utah.|ARUP Laboratories, Salt Lake City, Utah.
Bryan L
BL
Krock
Department of Pathology, University of Utah, Salt Lake City, Utah.|ARUP Laboratories, Salt Lake City, Utah.
Rong
R
Mao
Department of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California.
Joseph J
JJ
Shen
D000483:Alleles; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008831:Microcephaly / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012640:Seizures / Q000235:genetics
C573230:BRAT1 protein, human; D009687:Nuclear Proteins
BRAT1 protein, human; apnea; epilepsy; intellectual disability; muscle hypertonia; reflex, abnormal