Background/Objectives: Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder frequently associated with other neuropsychiatric conditions, characterized by high clinical heterogeneity and a complex genetic background. Recent studies suggest that copy number variations (CNVs) may contribute to ADHD susceptibility, particularly when involving genes related to brain development, attention regulation, and impulse control. This study investigated the association between CNVs and ADHD phenotype by identifying patients with and without potential pathogenic CNVs. Methods: We evaluated 152 well-characterized ADHD pediatric patients through comprehensive clinical assessments, including dysmorphic features, brain MRI, EEG patterns, and cognitive testing. CNVs were identified using array Comparative Genomic Hybridization (array-CGH). Participants were classified as carrying potentially causative CNVs (PC-CNVs), non-causative CNVs (NC-CNVs), or without CNVs (W-CNVs) and statistically compared across clinical and neurodevelopmental measures. Results: CNVs were identified in 81 participants (53%), comprising 13 with PC-CNVs (8.5%) and 68 with NC-CNVs (44.7%). ADHD symptoms were pronounced across all groups, but PC-CNVs showed a higher burden of comorbidities, suggesting a stronger genetic contribution to ADHD complexity. Significant differences were observed in oppositional behavior, inattentive symptoms, brain MRI findings, and developmental language anomalies. Several CNVs involved genes previously implicated in neurodevelopmental disorders, supporting a potential genetic contribution to the clinical complexity of ADHD. Conclusions: This exploratory study supports the role of CNVs in ADHD susceptibility and highlights the value of genetic screening for understanding clinical variability. Larger studies are needed to clarify genotype–phenotype correlations in ADHD and to guide personalized clinical management.

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>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–protein 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’s phenotype and a definitive disease–gene 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.