Premium
BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood
Author(s) -
Horn Denise,
Weschke Bernhard,
Knierim Ellen,
FischerZirnsak Björn,
Stenzel Werner,
Schuelke Markus,
Zemojtel Tomasz
Publication year - 2016
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.37798
Subject(s) - frameshift mutation , microcephaly , sanger sequencing , compound heterozygosity , muscle biopsy , encephalopathy , mutation , phenotype , genetics , hypertonia , exon , biology , medicine , pathology , gene , biopsy , neuroscience
We describe two siblings who were affected with early onset focal seizures, severe progressive postnatal microcephaly, muscular hypertonia, feeding problems and bouts of apnea, only minimal psychomotor development, as well as death in infancy and childhood. We identified compound heterozygous mutations in BRAT1 exons 5 (c.638_639insA) and 8 (c.1134+1G>A) in one affected child via next‐generation sequencing of the disease‐associated genome followed by phenotype‐driven bioinformatic analysis. Sanger sequencing confirmed the presence of these mutations in both patients and a heterozygote status of the parents. Whereas the frameshift mutation (c.638_639insA) has been described in one family, the splice‐site mutation (c.1134+1G>A) is novel. In contrast to all cases published so far, one of our patients showed a considerably milder clinical course with survival into childhood. Investigation of a skeletal muscle biopsy showed a severely reduced COX enzyme histochemical staining, indicating mitochondrial dysfunction. Our data expand the clinical and mutational spectrum of the BRAT1 ‐associated phenotype. © 2016 Wiley Periodicals, Inc.