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With an estimated heritability of 70\u201390%, ASD is highly familial, indicating that genetic factors play a significant role in its development. This shows how hundreds of genetic variants contribute to ASD, whose risk effects are highly variable and are often related to other conditions; these genetic alterations are at different levels, which include single gene mutations, monogenic disorders, genomic variants, and chromosomal abnormalities. Copy number variants (CNVs) appear to contribute significantly to understanding the pathogenesis of this complex disease. In some cases, single CNVs in genomic DNA are pathogenic and causative, supporting the hypothesis that some sporadic cases of ASD may result from rare mutations with significant clinical impact. However, in many cases, there are common genomic variants that increase the risk of developing ASD but are insufficient by themselves to determine an ASD phenotype, and rare genomic variants, of various sizes, inherited from a parent or de novo, that can be associated with the ASD phenotype. Therefore, the aim of this review is to deepen the concept of ASD inheritance through the two-hit theory of CNVs, in which the concomitant presence of two alterations could determine the clinical phenotypes, the concept of incomplete penetrance for inherited CNVs with pathogenic clinical significance, and the presence of compound heterozygosity. These aspects represent important mechanisms underlying the pathogenesis of autism, contributing to a better elucidation for the understanding of the genetic contribution to the ASD phenotype.<\/jats:p>","DOI":"10.3390\/genes16050478","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T10:40:48Z","timestamp":1745404848000},"page":"478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Autism Spectrum Disorder: Genetic Mechanisms and Inheritance Patterns"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1072-3763","authenticated-orcid":false,"given":"Ilaria","family":"La Monica","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy"},{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, Via G. Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7321-9799","authenticated-orcid":false,"given":"Maria Rosaria","family":"Di Iorio","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, Via G. Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Sica","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy"},{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, Via G. 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