{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T18:29:30Z","timestamp":1757701770218,"version":"3.41.2"},"reference-count":38,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T00:00:00Z","timestamp":1595289600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Over half of children with rare genetic diseases remain undiagnosed despite maximal clinical evaluation and DNA\u2010based genetic testing. As part of an Undiagnosed Diseases Program applying transcriptome (RNA) sequencing to identify the causes of these unsolved cases, we studied a child with severe infantile osteopetrosis leading to cranial nerve palsies, bone deformities, and bone marrow failure, for whom whole\u2010genome sequencing was nondiagnostic.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed transcriptome (RNA) sequencing of whole blood followed by analysis of aberrant transcript isoforms and osteoclast functional studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a pathogenic deep intronic variant in <jats:italic>CLCN7<\/jats:italic> creating an unexpected, frameshifting pseudoexon causing complete loss of function. Functional studies, including osteoclastogenesis and bone resorption assays, confirmed normal osteoclast differentiation but loss of osteoclast function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This is the first report of a pathogenic deep intronic variant in <jats:italic>CLCN7<\/jats:italic>, and our approach provides a model for systematic identification of noncoding variants causing osteopetrosis\u2014a disease for which molecular\u2010genetic diagnosis can be pivotal for potentially curative hematopoietic stem cell transplantation. Our work illustrates that cryptic splice variants may elude DNA\u2010only sequencing and supports broad first\u2010line use of transcriptome sequencing for children with undiagnosed diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1405","type":"journal-article","created":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T11:12:17Z","timestamp":1595329937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Transcriptome sequencing identifies a noncoding, deep intronic variant in <i>CLCN7<\/i> causing autosomal recessive osteopetrosis"],"prefix":"10.1002","volume":"8","author":[{"given":"Odelia","family":"Chorin","sequence":"first","affiliation":[{"name":"Center for Human Genetics and Genomics New York University Grossman School of Medicine New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Yachelevich","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetic Services Department of Pediatrics New York University Grossman School of Medicine New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Nordic Bioscience Biomarkers and Research Herlev Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilana","family":"Moscatelli","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine and Gene Therapy Lund University Lund Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Pappas","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetic Services Department of Pediatrics New York University Grossman School of Medicine New York NY USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Henriksen","sequence":"additional","affiliation":[{"name":"Nordic Bioscience Biomarkers and Research Herlev Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7621-2630","authenticated-orcid":false,"given":"Gilad D.","family":"Evrony","sequence":"additional","affiliation":[{"name":"Center for Human Genetics and Genomics New York University Grossman School of Medicine New York NY USA"},{"name":"Department of Pediatrics, and Department of Neuroscience &amp; 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