{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:41:39Z","timestamp":1760031699697,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH)","award":["U01-HG-009716","DC003594","H3A\/18\/001"],"award-info":[{"award-number":["U01-HG-009716","DC003594","H3A\/18\/001"]}]},{"name":"African Academy of Science\/Wellcome Trust","award":["U01-HG-009716","DC003594","H3A\/18\/001"],"award-info":[{"award-number":["U01-HG-009716","DC003594","H3A\/18\/001"]}]},{"name":"WACCBIP-World Bank African Centre of Excellence PhD fellowship (WACCBIP+NCDs)","award":["U01-HG-009716","DC003594","H3A\/18\/001"],"award-info":[{"award-number":["U01-HG-009716","DC003594","H3A\/18\/001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic studies and phenotypic expansion of hearing loss (HL) for people living in Africa are greatly needed. We evaluated the clinical phenotypes of three affected siblings presenting non-syndromic (NS) HL and five unaffected members of a consanguineous Ghanaian family. Analysis of exome sequence data was performed for all affected and one unaffected family members. In-depth genetic and cellular characterization studies were performed to investigate biological significance of the implicated variant using bioinformatic tools and cell-based experimentation. Audiological examinations showed severe-to-profound, bilateral, symmetrical, and post-lingual onset. The whole-exome sequencing (WES) identified a homozygous frameshift variant: MARVEL domain containing 2 (MARVELD2):c.1058dup;p.(Val354Serfs*5) in all affected siblings. This frameshift variant leads to an early stop codon insertion and predicted to be targeted by nonsense medicated decay (mutant protein predicted to lack conserved C-terminal domain if translated). Cell immunofluorescence and immunocytochemistry studies exposed the functional impact of the mutant protein\u2019s expression, stability, localization, protein\u2013protein binding, barrier function, and actin cytoskeleton architecture. The identified variant segregates with NSHL in the index Ghanaian family. The data support this nonsense variant as pathogenic, likely to impact the homeostasis of ions, solutes, and other molecules, compromising membrane barrier and signaling in the inner ear spaces.<\/jats:p>","DOI":"10.3390\/ijms26073337","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T05:51:26Z","timestamp":1743659486000},"page":"3337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bi-Allelic MARVELD2 Variant Identified with Exome Sequencing in a Consanguineous Multiplex Ghanaian Family Segregating Non-Syndromic Hearing Loss"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2994-3761","authenticated-orcid":false,"given":"Elvis","family":"Twumasi Aboagye","sequence":"first","affiliation":[{"name":"Department of Pathology, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"},{"name":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Legon, Accra LG 54, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1993-2786","authenticated-orcid":false,"given":"Samuel Mawuli","family":"Adadey","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-2399","authenticated-orcid":false,"given":"Leonardo","family":"Alves de Souza Rios","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Haematology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin K.","family":"Esoh","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"},{"name":"McKusick-Nathans Institute & Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3625-5059","authenticated-orcid":false,"given":"Edmond","family":"Wonkam-Tingang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-7182","authenticated-orcid":false,"given":"Lettilia","family":"Xhakaza","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4509-3162","authenticated-orcid":false,"given":"Carmen","family":"De Kock","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-6082","authenticated-orcid":false,"given":"Isabelle","family":"Schrauwen","sequence":"additional","affiliation":[{"name":"Department of Translational Neurosciences, University of Arizona College of Medicine Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4468-0506","authenticated-orcid":false,"given":"Lucas","family":"Amenga-Etego","sequence":"additional","affiliation":[{"name":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Legon, Accra LG 54, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-2079","authenticated-orcid":false,"given":"Dirk","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Human Biology, Division of Cell Biology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon A.","family":"Awandare","sequence":"additional","affiliation":[{"name":"West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Legon, Accra LG 54, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne M.","family":"Leal","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Centre, New York, NY 10032, USA"},{"name":"Taub Institute, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6802-0495","authenticated-orcid":false,"given":"Shaheen","family":"Mowla","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Haematology, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1420-9051","authenticated-orcid":false,"given":"Ambroise","family":"Wonkam","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa"},{"name":"McKusick-Nathans Institute & Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"ref_1","unstructured":"(2023). 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