@article{df39932a2f3543beb27169ff6e53855d,
title = "Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy",
abstract = "Objective: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. Methods: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. Results: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. Interpretation: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.",
author = "{Undiagnosed Diseases Network} and Sandra Donkervoort and Payam Mohassel and Melanie O'Leary and Bonner, {Devon E.} and Taila Hartley and Nicole Acquaye and Astrid Brull and Tahseen Mozaffar and Saporta, {Mario A.} and Dyment, {David A.} and Sampson, {Jacinda B.} and Sander Pajusalu and Christina Austin-Tse and Kyle Hurth and Cohen, {Julie S.} and Kirsty McWalter and Jodi Warman-Chardon and Amy Crunk and Foley, {A. Reghan} and Acosta, {Maria T.} and Adams, {David R.} and Alvarez, {Raquel L.} and Justin Alvey and Aimee Allworth and Ashley Andrews and Ashley, {Euan A.} and Ben Afzali and Bacino, {Carlos A.} and Guney Bademci and Ashok Balasubramanyam and Dustin Baldridge and Jim Bale and Michael Bamshad and Deborah Barbouth and Pinar Bayrak-Toydemir and Anita Beck and Beggs, {Alan H.} and Edward Behrens and Gill Bejerano and Bellen, {Hugo J.} and Jimmy Bennett and Bernstein, {Jonathan A.} and Berry, {Gerard T.} and Anna Bican and Stephanie Bivona and Elizabeth Blue and John Bohnsack and Devon Bonner and Lorenzo Botto and Briere, {Lauren C.} and Gabrielle Brown and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Butte, {Manish J.} and Peter Byers and Byrd, {William E.} and John Carey and Thomas Cassini and Sirisak Chanprasert and Chao, {Hsiao Tuan} and Ivan Chinn and Clark, {Gary D.} and Coakley, {Terra R.} and Cobban, {Laurel A.} and Cogan, {Joy D.} and Matthew Coggins and Sessions Cole and Colley, {Heather A.} and Rosario Corona and Craigen, {William J.} and Crouse, {Andrew B.} and Michael Cunningham and Precilla D'Souza and Hongzheng Dai and Surendra Dasari and Joie Davis and Dayal, {Jyoti G.} and Margaret Delgado and Dell'Angelica, {Esteban C.} and Katrina Dipple and Daniel Doherty and Naghmeh Dorrani and Doss, {Argenia L.} and Douine, {Emilie D.} and Dawn Earl and Eckstein, {David J.} and Emrick, {Lisa T.} and Eng, {Christine M.} and Marni Falk and Fieg, {Elizabeth L.} and Fisher, {Paul G.} and Fogel, {Brent L.} and Jiayu Fu and Gahl, {William A.} and Ian Glass and Goddard, {Page C.} and Godfrey, {Rena A.} and Andrea Gropman and Halley, {Meghan C.} and Rizwan Hamid and Neal Hanchard and Kelly Hassey and Nichole Hayes and Frances High and Anne Hing and Hisama, {Fuki M.} and Holm, {Ingrid A.} and Jason Hom and Martha Horike-Pyne and Alden Huang and Yan Huang and Sarah Hutchison and Wendy Introne and Kosuke Izumi and Jarvik, {Gail P.} and Jeffrey Jarvik and Suman Jayadev and Orpa Jean-Marie and Vaidehi Jobanputra and Emerald Kaitryn and Shamika Ketkar and Dana Kiley and Gonench Kilich and Kobren, {Shilpa N.} and Kohane, {Isaac S.} and Kohler, {Jennefer N.} and Susan Korrick and Deborah Krakow and Krasnewich, {Donna M.} and Elijah Kravets and Lalani, {Seema R.} and Christina Lam and Lanpher, {Brendan C.} and Lanza, {Ian R.} and Kimberly LeBlanc and Lee, {Brendan H.} and Lewis, {Richard A.} and Pengfei Liu and Nicola Longo and Loo, {Sandra K.} and Joseph Loscalzo and Maas, {Richard L.} and Macnamara, {Ellen F.} and MacRae, {Calum A.} and Maduro, {Valerie V.} and Maghiro, {Audrey Stephannie} and Rachel Mahoney and Malicdan, {May Christine V.} and Mamounas, {Laura A.} and Manolio, {Teri A.} and Rong Mao and Ronit Marom and Gabor Marth and Martin, {Beth A.} and Martin, {Martin G.} and Mart{\'i}nez-Agosto, {Julian A.} and Shruti Marwaha and Allyn McConkie-Rosell and McCray, {Alexa T.} and Elisabeth McGee and Matthew Might and Mohamad Mikati and Danny Miller and Ghayda Mirzaa and Eva Morava and Paolo Moretti and Marie Morimoto and Mulvihill, {John J.} and Mariko Nakano-Okuno and Nelson, {Stanley F.} and Shirley Nieves-Rodriguez and Donna Novacic and Devin Oglesbee and Orengo, {James P.} and Laura Pace and Stephen Pak and Pallais, {J. Carl} and Papp, {Jeanette C.} and Parker, {Neil H.} and Leoyklang Petcharet and Phillips, {John A.} and Posey, {Jennifer E.} and Lorraine Potocki and {Pusey Swerdzewski}, {Barbara N.} and Aaron Quinlan and Rao, {Deepak A.} and Anna Raper and Wendy Raskind and Genecee Renteria and Reuter, {Chloe M.} and Lynette Rives and Robertson, {Amy K.} and Rodan, {Lance H.} and Rosenfeld, {Jill A.} and Elizabeth Rosenthal and Francis Rossignol and Timothy Schedl and Jimann Shin and Lilianna Solnica-Krezel and Jennifer Wambach",
note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.",
year = "2024",
month = mar,
doi = "10.1002/acn3.51983",
language = "English",
volume = "11",
pages = "629--640",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
number = "3",
}