{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:57:21Z","timestamp":1793228241060,"version":"4.5.0"},"reference-count":5,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T00:00:00Z","timestamp":1740355200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Kohlsch\u00fctter\u2010T\u00f6nz Syndrome (KTS) is an ultra\u2010rare autosomal recessive disorder, characterized by a clinical triad: infantile\u2010onset epilepsy, global developmental delay, and amelogenesis imperfecta. KTS is caused by pathogenic variants in <jats:italic>ROGDI<\/jats:italic>, encoding a leucine zipper protein of unknown function. Our study characterizes a novel homozygous <jats:italic>ROGDI<\/jats:italic> variant (NM_024589.3:c.646\u20102A&gt;G) identified in a Tunisian family case with KTS, renal tubular acidosis, and hyperammonemia. This variant disrupts a canonical acceptor splice site (ASS) in intron 8. Reverse\u2010transcriptase polymerase chain reaction and targeted long\u2010read cDNA sequencing, identified only abnormal transcripts secondary to the <jats:italic>ROGDI<\/jats:italic> ASS variant in the proband. Complex splicing events were detected including exon 9 skipping, cryptic ASS activation leading to 13\u2010bp deletion in exon 9, and retention of intron 8 or both intron 8 and 9. These alterations were all predicted to result in nonsense mediated decay and <jats:italic>ROGDI<\/jats:italic> loss of function. By integrating complementary techniques, our study unveiled fundamental mechanisms underlying complex splice alterations, providing insights that may guide future therapeutic strategies in KTS.<\/jats:p>","DOI":"10.1111\/cge.14725","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T16:02:00Z","timestamp":1741708920000},"page":"705-707","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Transcript Long\u2010Read Sequencing Unveils the Molecular Complexity of a Novel <i>ROGDI<\/i> Splicing Variant in a Tunisian Family With Kohlsch\u00fctter\u2010T\u00f6nz Syndrome"],"prefix":"10.1111","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8129-164X","authenticated-orcid":false,"given":"Miriam","family":"Essid","sequence":"first","affiliation":[{"name":"Genetics Department Hospices Civils de Lyon  Lyon France"},{"name":"Neuromyogene Institute, Pathology and Genetics of Neuron and Muscle, CNRS UMR 5261 INSERM U1315 Universit\u00e9 Claude Bernard Lyon 1  Lyon France"},{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Karoui","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Genetic Department LR22SP01, Mongi Slim Hospital  La Marsa Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouna","family":"Zribi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Department of Pediatrics and Hereditary Metabolic Diseases LR12SP02, La Rabta Hospital  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1475-938X","authenticated-orcid":false,"given":"Thouraya","family":"Ben Younes","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Department of Child and Adolescent Neurology LR18SP04, National Institute Mongi Ben Hmida of Neurology  La Rabta Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Januel","sequence":"additional","affiliation":[{"name":"Genetics Department Hospices Civils de Lyon  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Lafont","sequence":"additional","affiliation":[{"name":"Genetics Department Hospices Civils de Lyon  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Labalme","sequence":"additional","affiliation":[{"name":"Genetics Department Hospices Civils de Lyon  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriem","family":"Ben Hafsa","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Department of Child and Adolescent Neurology LR18SP04, National Institute Mongi Ben Hmida of Neurology  La Rabta Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Hun Seo","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics 3billion Inc.  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safa","family":"Khatrouch","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Department of Pediatrics and Hereditary Metabolic Diseases LR12SP02, La Rabta Hospital  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hela","family":"Boudabous","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Department of Pediatrics and Hereditary Metabolic Diseases LR12SP02, La Rabta Hospital  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amel","family":"Ben Chehida","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Department of Pediatrics and Hereditary Metabolic Diseases LR12SP02, La Rabta Hospital  Tunis Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Sanlaville","sequence":"additional","affiliation":[{"name":"Genetics Department Hospices Civils de Lyon  Lyon France"},{"name":"Neuromyogene Institute, Pathology and Genetics of Neuron and Muscle, CNRS UMR 5261 INSERM U1315 Universit\u00e9 Claude Bernard Lyon 1  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houweyda","family":"Jilani","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Genetic Department LR22SP01, Mongi Slim Hospital  La Marsa Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamia","family":"Benjemaa","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Genetic Department LR22SP01, Mongi Slim Hospital  La Marsa Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6942-5662","authenticated-orcid":false,"given":"Ichraf","family":"Kraoua","sequence":"additional","affiliation":[{"name":"Faculty of Medicine of Tunis University of Tunis El Manar  Tunis Tunisia"},{"name":"Department of Child and Adolescent Neurology LR18SP04, National Institute Mongi Ben Hmida of Neurology  La Rabta Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetan","family":"Lesca","sequence":"additional","affiliation":[{"name":"Genetics Department Hospices Civils de Lyon  Lyon France"},{"name":"Neuromyogene Institute, Pathology and Genetics of Neuron and Muscle, CNRS UMR 5261 INSERM U1315 Universit\u00e9 Claude Bernard Lyon 1  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-0981","authenticated-orcid":false,"given":"Nicolas","family":"Chatron","sequence":"additional","affiliation":[{"name":"Genetics Department Hospices Civils de Lyon  Lyon France"},{"name":"Neuromyogene Institute, Pathology and Genetics of Neuron and Muscle, CNRS UMR 5261 INSERM U1315 Universit\u00e9 Claude Bernard Lyon 1  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62613"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.02.012"},{"issue":"4","key":"e_1_2_6_4_1","first-page":"283","article-title":"Familial Epilepsy and Yellow Teeth\u2014A Disease of the CNS Associated With Enamel Hypoplasia","volume":"29","author":"Kohlsch\u00fctter A.","year":"1974","journal-title":"Helvetica 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