{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:51:01Z","timestamp":1786978261620,"version":"build-2736575974"},"reference-count":67,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["RN127580 \u2010 260005"],"award-info":[{"award-number":["RN127580 \u2010 260005"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008644","name":"Faculty of Medicine, McGill University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008644","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"Fonds de Recherche du Qu\u00e9bec - Sant\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2021,7]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that\n SPG7<\/jats:italic>\n variants may also cause autosomal dominant hereditary spastic paraplegia (HSP).\n <\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n \n We aimed to conduct an exome\u2010wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of\n SPG7<\/jats:italic>\n and HSP.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole\u2010exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The frequency of heterozygous pathogenic\/likely pathogenic\n SPG7<\/jats:italic>\n variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR\u20092.88, 95% CI\u20091.24\u20136.66,\n P<\/jats:italic>\n \u00a0=\u00a00.009). The heterozygous\n SPG7<\/jats:italic>\n p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR\u20094.42, 95% CI\u20091.49\u201313.07,\n P<\/jats:italic>\n \u00a0=\u00a00.005). Similar results were obtained after including only genetically\u2010undiagnosed patients. We identified four heterozygous\n SPG7<\/jats:italic>\n variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR\u200919.58, 95% CI\u20091.05\u2013365.13,\n P<\/jats:italic>\n \u00a0=\u00a00.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in\n SPG7<\/jats:italic>\n and\n SPG7<\/jats:italic>\n \u2010interacting genes (\n CACNA1A<\/jats:italic>\n ,\n AFG3L2,<\/jats:italic>\n and\n MORC2<\/jats:italic>\n ). Of these, there is especially compelling evidence for epistasis between\n SPG7<\/jats:italic>\n and\n AFG3L2<\/jats:italic>\n . The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our results provide evidence for complex inheritance in\n SPG7<\/jats:italic>\n \u2010associated HSP, which may include recessive and possibly dominant and digenic\/epistasis forms of inheritance. \u00a9 2021 International Parkinson and Movement Disorder Society\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mds.28528","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T10:06:35Z","timestamp":1613815595000},"page":"1664-1675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Evidence for Non\u2010Mendelian Inheritance in Spastic Paraplegia 7"],"prefix":"10.1002","volume":"36","author":[{"given":"Mehrdad A.","family":"Estiar","sequence":"first","affiliation":[{"name":"Department of Human Genetics McGill University Montr\u00e9al Qu\u00e9bec Canada"},{"name":"The Neuro (Montreal Neurological Institute\u2010Hospital) McGill University Montr\u00e9al Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Montr\u00e9al Qu\u00e9bec Canada"},{"name":"The Neuro (Montreal Neurological Institute\u2010Hospital) McGill University Montr\u00e9al Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikhlass","family":"Haj Salem","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de M\u00e9decine Universit\u00e9 Laval Quebec City Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay P.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Montr\u00e9al Qu\u00e9bec Canada"},{"name":"The Neuro (Montreal Neurological Institute\u2010Hospital) McGill University Montr\u00e9al Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kheireddin","family":"Mufti","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Montr\u00e9al Qu\u00e9bec Canada"},{"name":"The Neuro (Montreal Neurological Institute\u2010Hospital) McGill University Montr\u00e9al Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulya","family":"Ak\u00e7imen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics McGill University Montr\u00e9al Qu\u00e9bec Canada"},{"name":"The Neuro (Montreal Neurological Institute\u2010Hospital) McGill University Montr\u00e9al Qu\u00e9bec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Leveille","sequence":"additional","affiliation":[{"name":"Faculty 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