{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:01:11Z","timestamp":1784955671513,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Attention-deficit\/hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterized by a complex and multifactorial genetic architecture. In this study, we report a male patient, born to non-consanguineous healthy parents, presenting with ADHD and oppositional defiant disorder (ODD). Methods: Trio-based whole-exome sequencing (WES) was performed in the proband and both parents. Variant classification was performed according to American College of Medical Genetics and Genomics (ACMG) guidelines, and the potential pathogenicity of the identified variant was further assessed through multiple in silico prediction algorithms and protein structural analyses. Results: WES identified a homozygous variant in the LNX2 gene (NM_153371.4: c.1165G&gt;A, p.Ala389Thr), classified as a variant of uncertain significance (VUS) and supported by multiple in silico predictions. LNX2 is expressed during brain development and encodes an E3 ubiquitin ligase involved in neuronal differentiation and synaptic function. The identified variant is located within the PDZ2 domain, a functionally relevant region involved in protein\u2013protein interactions. Although the variant is reported in population databases (gnomAD ID: rs148429804), it has not been associated with any clinical phenotype, and its presence in the homozygous state has been reported only once, remaining extremely rare and lacking clinical annotation. Structural modelling predicted localized rearrangement of the hydrogen-bonding network within the PDZ2 domain without major conformational changes. Integrative transcriptomic, and single-cell analyses further supported the biological relevance of LNX2 in neurodevelopment, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs. Conclusion: Although the identified LNX2 variant cannot be considered causative for the patient\u2019s phenotype and a definitive disease\u2013gene relationship cannot be established based on a single individual, the complementary genetic, structural, and transcriptomic findings support the biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders. Additional independent patients and functional studies will be required to clarify its contribution to human disease.<\/jats:p>","DOI":"10.3390\/genes17080849","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:13:17Z","timestamp":1784826797000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Role of LNX2 as a Potential Contributor to Neurodevelopmental Disorders"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3026-8510","authenticated-orcid":false,"given":"Mirella","family":"Vinci","sequence":"first","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Figura","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8999-3365","authenticated-orcid":false,"given":"Antonino","family":"Musumeci","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6465-2998","authenticated-orcid":false,"given":"Miriam","family":"Virgillito","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1958-7409","authenticated-orcid":false,"given":"Valentina","family":"Finocchiaro","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5631-9991","authenticated-orcid":false,"given":"Simone","family":"Treccarichi","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7399-964X","authenticated-orcid":false,"given":"Alda","family":"Ragalmuto","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1927-9465","authenticated-orcid":false,"given":"Antonio","family":"Fallea","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Federico","sequence":"additional","affiliation":[{"name":"Department of Biological, Geological and Environmental Sciences, University of Catania, 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7568-5823","authenticated-orcid":false,"given":"Salvatore","family":"Saccone","sequence":"additional","affiliation":[{"name":"Department of Biological, Geological and Environmental Sciences, University of Catania, 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8667-8223","authenticated-orcid":false,"given":"Francesco","family":"Cal\u00ec","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, 94018 Troina, Italy"},{"name":"Department Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1111\/jcpp.13659","article-title":"Mother\u2019s and Children\u2019s ADHD Genetic Risk, Household Chaos and Children\u2019s ADHD Symptoms: A Gene\u2013Environment Correlation Study","volume":"63","author":"Wertz","year":"2022","journal-title":"Child Psychol. 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