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Biallelic mutations in <jats:italic>CAPN3<\/jats:italic> are reported frequently to cause LGMDR1. Here, we describe 11 individuals from three unrelated consanguineous families that present with typical features of LGMDR1 that include proximal muscle wasting, weakness of the upper and lower limbs, and elevated serum creatine kinase. Whole\u2010exome sequencing identified a rare homozygous <jats:italic>CAPN3<\/jats:italic> variant near the exon 2 splice donor site that segregates with disease in all three families. mRNA splicing studies showed partial retention of intronic sequence and subsequent introduction of a premature stop codon (NM_000070.3: c.379\u2009+\u20093A&gt;G; p.Asp128Glyfs*15). Furthermore, we observe reduced <jats:italic>CAPN3<\/jats:italic> expression in primary dermal fibroblasts derived from an affected individual, suggesting instability and\/or nonsense\u2010mediated decay of mutation\u2010bearing mRNA. Genome\u2010wide homozygosity mapping and single\u2010nucleotide polymorphism analysis identified a shared haplotype and supports a possible founder effect for the <jats:italic>CAPN3<\/jats:italic> variant. Together, our data extend the mutational spectrum of LGMDR1 and have implications for improved diagnostics for individuals of Pakistani origin.<\/jats:p>","DOI":"10.1002\/ajmg.a.62545","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T06:00:47Z","timestamp":1635228047000},"page":"498-508","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A recurrent rare intronic variant in <scp><i>CAPN3<\/i><\/scp> alters <scp>mRNA<\/scp> splicing and causes autosomal recessive limb\u2010girdle muscular dystrophy\u20101 in three Pakistani pedigrees"],"prefix":"10.1002","volume":"188","author":[{"given":"Kamal","family":"Khan","sequence":"first","affiliation":[{"name":"Center for Human Disease Modeling, Duke University Medical Center  Durham North Carolina USA"},{"name":"Stanley Manne Children's Research Institute, Ann &amp; Robert H. 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\u2010 Level 4, Royal Devon and Exeter NHS Foundation Trust, University of Exeter Medical School  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma A.","family":"Baple","sequence":"additional","affiliation":[{"name":"RILD Wellcome Wolfson Centre \u2010 Level 4, Royal Devon and Exeter NHS Foundation Trust, University of Exeter Medical School  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad I.","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences College of Applied Medical Sciences, Jouf University  Sakaka Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaineb","family":"Akram","sequence":"additional","affiliation":[{"name":"Stem Cell Research Laboratory, AFBMTC, CMH Medical Complex  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humayoon S.","family":"Satti","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences National University of Medical Sciences  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raees","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences National University of Medical Sciences  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav V.","family":"Harlalka","sequence":"additional","affiliation":[{"name":"RILD Wellcome Wolfson Centre \u2010 Level 4, Royal Devon and Exeter NHS Foundation Trust, University of Exeter Medical School  Exeter UK"},{"name":"Department of Pharmacology Rajarshi Shahu College of Pharmacy  Malvihir, Buldana Maharashtra India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Jameel","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division National Institute for Biotechnology and Genetic Engineering College (NIBGE\u2010C)  Faisalabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Akram","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division National Institute for Biotechnology and Genetic Engineering College (NIBGE\u2010C)  Faisalabad Pakistan"},{"name":"Pakistan Institute of Engineering and Applied Sciences (PIEAS)  Islamabad Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid M.","family":"Baig","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division National Institute for Biotechnology and Genetic Engineering College (NIBGE\u2010C)  Faisalabad Pakistan"},{"name":"Pakistan Institute of Engineering and Applied Sciences (PIEAS)  Islamabad Pakistan"},{"name":"Pakistan Science Foundation  Islamabad Pakistan"},{"name":"Department of Biological and Biomedical Sciences Aga Khan University  Karachi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew H.","family":"Crosby","sequence":"additional","affiliation":[{"name":"RILD Wellcome Wolfson Centre \u2010 Level 4, Royal Devon and Exeter NHS Foundation Trust, University of Exeter Medical School  Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad J.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Atta\u2010ur\u2010Rahman School of Applied Biosciences, National University of Sciences and Technology  Islamabad Pakistan"},{"name":"Department of Biological Sciences National University of Medical Sciences  Rawalpindi Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical 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