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delay, organomegaly, hypogammaglobulinemia and hypopigmentation without osteopetrosis. Whole\u2010exome sequencing revealed a de novo gain\u2010of\u2010function variant, p.Tyr715Cys, in the C\u2010terminal domain of ClC\u20107 encoded by <jats:italic>CLCN7<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Nicoli et\u00a0al. (2019) assessed the functional impact of p.Tyr715Cys by heterologous expression in Xenopus oocytes and evaluating resulting currents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The variant led to increased outward currents, indicating it underlies the patient's phenotype of lysosomal hyperacidity, storage defects and vacuolization. This demonstrates the crucial physiological role of ClC\u20107 antiporter activity in maintaining appropriate lysosomal pH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Elucidating mechanisms by which <jats:italic>CLCN7<\/jats:italic> variants lead to lysosomal dysfunction will advance understanding of genotype\u2013phenotype correlations. Identifying modifier genes and compensatory pathways may reveal therapeutic targets. Ongoing functional characterization of variants along with longitudinal clinical evaluations will continue advancing knowledge of ClC\u20107's critical roles and disease mechanisms resulting from its dysfunction. Expanded cohort studies are warranted to delineate the full spectrum of associated phenotypes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2494","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T12:05:15Z","timestamp":1721995515000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multisystem disorder associated with a pathogenic variant in <scp><i>CLCN7<\/i><\/scp> in the absence of osteopetrosis"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8178-6938","authenticated-orcid":false,"given":"Chung\u2010Lin","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department and Institute of Clinical Medicine National Yang\u2010Ming Chiao\u2010Tung University  Taipei Taiwan"},{"name":"Department of Rare Disease Center MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Medicine Mackay Medical College  New Taipei City Taiwan"},{"name":"Mackay Junior College of Medicine, Nursing, and Management  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeun\u2010Wen","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Pediatrics Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9619-0990","authenticated-orcid":false,"given":"Hsiang\u2010Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Rare Disease Center MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Medicine Mackay Medical College  New Taipei City Taiwan"},{"name":"Mackay Junior College of Medicine, Nursing, and Management  Taipei Taiwan"},{"name":"Division of Genetics and Metabolism, Department of Medical Research MacKay Memorial Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-7499","authenticated-orcid":false,"given":"Hung\u2010Chang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting\u2010Chi","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Ching","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni\u2010Chung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics National Taiwan University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeng\u2010Daw","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Medicine Mackay Medical College  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuan\u2010Pei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Rare Disease Center MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Medicine Mackay Medical College  New Taipei City Taiwan"},{"name":"Division of Genetics and Metabolism, Department of Medical Research MacKay Memorial Hospital  Taipei Taiwan"},{"name":"Department of Infant and Child Care National Taipei University of Nursing and Health Sciences  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,26]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.2001.5260"},{"key":"e_1_2_13_3_1","unstructured":"Andrews S.FastQC: a quality control tool for high throughput sequence data.2010. 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