title: Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria.
abstract: Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1.
authors.affiliation: Centre for Medical Research, The University of Western Australia and Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia. Electronic address: gina.ravenscroft@perkins.uwa.edu.au.
authors.forename: Gianina
authors.initials: G
authors.lastname: Ravenscroft
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, TU Dresden, Dresden, Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Di Donato
authors.affiliation: Institut und Poliklinik für Radiologische Diagnostik, Universitätsklinikum Dresden, Dresden, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hahn
authors.affiliation: Department of Diagnostic Genomics, Pathwest, Nedlands, Western Australia, Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Davis
authors.affiliation: John Hunter Children's Hospital, Hunter Valley, New South Wales, Australia.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Craven
authors.affiliation: Genetic Health Services, Auckland, New Zealand.
authors.forename: Gemma
authors.initials: G
authors.lastname: Poke
authors.affiliation: Genetic Health Services, Auckland, New Zealand.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Neas
authors.affiliation: Medizinisch Genetisches Zentrum, Munich, Germany.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Neuhann
authors.affiliation: Seattle Children's Research Institute, Seattle, WA, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Centre for Medical Research, The University of Western Australia and Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia; Department of Diagnostic Genomics, Pathwest, Nedlands, Western Australia, Australia.
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D001176:Arthrogryposis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D002675:Child, Preschool; D017809:Fatal Outcome; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D008297:Male; D054220:Malformations of Cortical Development / Q000000981:diagnostic imaging / Q000235:genetics* / Q000628:therapy; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype
chemical_list: C561542:BICD2 protein, human; D008869:Microtubule-Associated Proteins
keywords: Arthrogryposis; BICD2; Fetal akinesia; Perisylvian polymicrogyria