title: Whole exome sequencing in foetal akinesia expands the genotype-phenotype spectrum of GBE1 glycogen storage disease mutations.
abstract: The clinically and genetically heterogenous foetal akinesias have low rates of genetic diagnosis. Exome sequencing of two siblings with phenotypic lethal multiple pterygium syndrome identified compound heterozygozity for a known splice site mutation (c.691+2T>C) and a novel missense mutation (c.956A>G; p.His319Arg) in glycogen branching enzyme 1 (GBE1). GBE1 mutations cause glycogen storage disease IV (GSD IV), including a severe foetal akinesia sub-phenotype. Re-investigating the muscle pathology identified storage material, consistent with GSD IV, which was confirmed biochemically. This study highlights the power of exome sequencing in genetically heterogeneous diseases and adds multiple pterygium syndrome to the phenotypic spectrum of GBE1 mutation.
authors.affiliation: Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia. gina.ravenscroft@uwa.edu.au
authors.forename: Gianina
authors.initials: G
authors.lastname: Ravenscroft
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Thompson
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Todd
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Yau
authors.forename: Nina
authors.initials: N
authors.lastname: Kresoje
authors.forename: Padma
authors.initials: P
authors.lastname: Sivadorai
authors.forename: Kathryn
authors.initials: K
authors.lastname: Friend
authors.forename: Kate
authors.initials: K
authors.lastname: Riley
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Manton
authors.forename: Peter
authors.initials: P
authors.lastname: Blumbergs
authors.forename: Michael
authors.initials: M
authors.lastname: Fietz
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Duff
authors.forename: Mark R
authors.initials: MR
authors.lastname: Davis
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Allcock
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000595:Amino Acid Sequence; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D001315:Australia; D001706:Biopsy; D059472:Exome / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005838:Genotype; D006004:Glycogen Debranching Enzyme System / Q000235:genetics*; D006008:Glycogen Storage Disease / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008305:Malignant Hyperthermia / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012868:Skin Abnormalities / Q000175:diagnosis / Q000235:genetics*
chemical_list: D006004:Glycogen Debranching Enzyme System; C577876:GBE1 protein, human