Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1

Szabolcs Szelinger; Jonida Krate; Keri Ramsey; Samuel P Strom; Perry B Shieh; Hane Lee; Newell Belnap; Chris Balak; Ashley L Siniard; Megan Russell; Ryan Richholt; Matt De Both; Ana M Claasen; Isabelle Schrauwen; Stanley F Nelson; Matthew J Huentelman; David W Craig; Samuel P Yang; Steven A Moore; Kumaraswamy Sivakumar; Vinodh Narayanan; Sampathkumar Rangasamy; UCLA Clinical Genomics Center

doi:10.1212/NXG.0000000000000468

Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1

Neurol Genet. 2020 Jun 30;6(4):e468. doi: 10.1212/NXG.0000000000000468. eCollection 2020 Aug.

Authors

Szabolcs Szelinger¹, Jonida Krate¹, Keri Ramsey¹, Samuel P Strom¹, Perry B Shieh¹, Hane Lee¹, Newell Belnap¹, Chris Balak¹, Ashley L Siniard¹, Megan Russell¹, Ryan Richholt¹, Matt De Both¹, Ana M Claasen¹, Isabelle Schrauwen¹, Stanley F Nelson¹, Matthew J Huentelman¹, David W Craig¹, Samuel P Yang¹, Steven A Moore¹, Kumaraswamy Sivakumar¹, Vinodh Narayanan¹, Sampathkumar Rangasamy¹; UCLA Clinical Genomics Center

Affiliation

¹ 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.

Abstract

Objective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) 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 GFPT1 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 GFPT1 mutations in CMS12 and in one family demonstrate a novel mode of inheritance due to UPD.

Abstract

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