Neurol Genet 2020 Aug 30;6(4):e468. Epub 2020 Jun 30.
theNeurogenomics Division (S.S., J.K., K.R., N.B., C.B., A.L.S., M.R., R.R., M.D.B., A.M.C., M.J.H, V.N., S.R.), Translational Genomics Research Institute, Center for Rare Childhood Disorders, Phoenix, AZ; Fulgent Genetics (S.P.S.), Temple City, CA; Department of Neurology (P.B.S.), University of California Los Angeles; David Geffen School of Medicine (P.B.S.), Los Angeles; Department of Pathology and Laboratory Medicine (H.L., S.F.N.), University of California, Los Angeles; Department of Human Genetics (H.L., S.F.N.), David Geffen School of Medicine; Department of Neurology (I.S.), Columbia University, Center for Statistical Genetics, New York; Department of Translational Genomics (D.W.C.), University of Southern California, Los Angeles; Providence Sacred Heart Medical Center and Children's Hospital (S.P.Y.), Spokane, WA; Department of Pathology (S.A.M), University of Iowa, Carver College of Medicine; and Neuromuscular Clinic and Research Center (K.S.), Phoenix, AZ.
Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 () gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.
Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed.
Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction. Genetic analysis identified a homozygous frameshift insertion in the gene (NM_001244710.1: c.686dupC; p.Arg230Ter) that was shared by all 3 patients. In one of the patients, inheritance of the variant was through uniparental disomy (UPD) with maternal origin. Repetitive nerve stimulation and single-fiber EMG was consistent with the clinical diagnosis of CMS with a postjunctional defect. Ultrastructural evaluation of the muscle biopsy from one of the patients showed extremely attenuated postsynaptic folds at neuromuscular junctions and extensive autophagic vacuolar pathology.
Conclusions: These results expand on the spectrum of known loss-of-function mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.