title: Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome.
abstract: BACKGROUND
  Foetal akinesia deformation sequence syndrome (FADS) is a genetically heterogeneous disorder characterised by the combination of foetal akinesia and developmental defects which may include pterygia (joint webbing). Traditionally multiple pterygium syndrome (MPS) has been divided into two forms: prenatally lethal (LMPS) and non-lethal Escobar type (EVMPS) types. Interestingly, FADS, LMPS and EVMPS may be allelic e.g. each of these phenotypes may result from mutations in the foetal acetylcholine receptor gamma subunit gene (CHRNG). Many cases of FADS and MPS do not have a mutation in a known FADS/MPS gene and we undertook molecular genetic studies to identify novel causes of these phenotypes.
  
  
  RESULTS
  After mapping a novel locus for FADS/LMPS to chromosome 19, we identified a homozygous null mutation in the RYR1 gene in a consanguineous kindred with recurrent LMPS pregnancies. Resequencing of RYR1 in a cohort of 66 unrelated probands with FADS/LMPS/EVMPS (36 with FADS/LMPS and 30 with EVMPS) revealed two additional homozygous mutations (in frame deletions). The overall frequency of RYR1 mutations in probands with FADS/LMPS was 8.3%.
  
  
  CONCLUSIONS
  Our findings report, for the first time, a homozygous RYR1 null mutation and expand the range of RYR1-related phenotypes to include early lethal FADS/LMPS. We suggest that RYR1 mutation analysis should be performed in cases of severe FADS/LMPS even in the absence of specific histopathological indicators of RYR1-related disease.
authors.affiliation: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. abm44@medschl.cam.ac.uk.
authors.forename: Arthur B
authors.initials: AB
authors.lastname: McKie
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. ASA195@student.bham.ac.uk.
authors.forename: Atif
authors.initials: A
authors.lastname: Alsaedi
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, B15 2TG, UK. Julie.Vogt@bwnft.nhs.uk.
authors.forename: Julie
authors.initials: J
authors.lastname: Vogt
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. k.stuurman@vumc.nl.
authors.forename: Kyra E
authors.initials: KE
authors.lastname: Stuurman
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. j.weiss@vumc.nl.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. hs470@cam.ac.uk.
authors.forename: Hassan
authors.initials: H
authors.lastname: Shakeel
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. L.Tee@bham.ac.uk.
authors.forename: Louise
authors.initials: L
authors.lastname: Tee
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. N.V.Morgan@bham.ac.uk.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. P.G.J.Nikkels@umcutrecht.nl.
authors.forename: Peter G J
authors.initials: PG
authors.lastname: Nikkels
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. G.vanHaaften@umcutrecht.nl.
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.affiliation: Department of Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. soo-mi.park@addenbrookes.nhs.uk.
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. j.j.vandersmagt@umcutrecht.nl.
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: van der Smagt
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands. m.bugiani@vumc.nl.
authors.forename: Marianna
authors.initials: M
authors.lastname: Bugiani
authors.affiliation: Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. erm1000@medschl.cam.ac.uk.|Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. erm1000@medschl.cam.ac.uk.|Department of Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, CB2 0QQ, UK. erm1000@medschl.cam.ac.uk.|Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Addenbrooke's Treatment Centre, Cambridge Biomedical Campus, Box 238, Cambridge, CB2 0QQ, United Kingdom. erm1000@medschl.cam.ac.uk.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D018389:Codon, Nonsense; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005190:Family; D005333:Fetus; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000473:pathology; D018895:Microsatellite Repeats; D018482:Muscle, Skeletal / Q000196:embryology / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017384:Sequence Deletion; D012868:Skin Abnormalities / Q000235:genetics* / Q000473:pathology
chemical_list: D018389:Codon, Nonsense; D019837:Ryanodine Receptor Calcium Release Channel