{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:28Z","timestamp":1786976848876,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,1,16]],"date-time":"2019-01-16T00:00:00Z","timestamp":1547596800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation\u2010contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the\n                    <jats:italic>RYR1<\/jats:italic>\n                    have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next\u2010generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with\n                    <jats:italic>RYR1<\/jats:italic>\n                    \u2010related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core\u2010rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)\/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous\/compound heterozygous\n                    <jats:italic>RYR1<\/jats:italic>\n                    gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35\u2010year\u2010old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35\u2009years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.61025","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T01:11:53Z","timestamp":1547687513000},"page":"386-396","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Homozygous\/compound heterozygote\n                    <i>RYR1<\/i>\n                    gene variants: Expanding the clinical spectrum"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9026-7002","authenticated-orcid":false,"given":"Ebba","family":"Alkhunaizi","sequence":"first","affiliation":[{"name":"The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital University of Toronto  Toronto Ontario Canada"},{"name":"Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Shuster","sequence":"additional","affiliation":[{"name":"The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Shannon","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Mount Sinai Hospital University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria Mok","family":"Siu","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, London Health Sciences Centre, Schulich School of Medicine and Dentistry Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Darilek","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine  Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie A","family":"Mohila","sequence":"additional","affiliation":[{"name":"Department of Pathology Texas Children's Hospital  Houston Texas"},{"name":"Department of Pathology and Immunology Baylor College of Medicine  Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Boissel","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics CHU Sainte\u2010Justine Research Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Ellezam","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics CHU Sainte\u2010Justine Research Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Fallet\u2010Bianco","sequence":"additional","affiliation":[{"name":"Department of Pathology CHU Sainte\u2010Justine  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Marie","family":"Laberge","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics CHU Sainte\u2010Justine Research Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianne","family":"Zandberg","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, London Health Sciences Centre, Schulich School of Medicine and Dentistry Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Injeyan","sequence":"additional","affiliation":[{"name":"The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili\u2010Naz","family":"Hazrati","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi","family":"Hamdan","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics CHU Sainte\u2010Justine Research Center  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1944-7294","authenticated-orcid":false,"given":"David","family":"Chitayat","sequence":"additional","affiliation":[{"name":"The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital University of Toronto  Toronto Ontario Canada"},{"name":"Department of Pediatrics, Division of 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