{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T04:50:49Z","timestamp":1782881449645,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"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>Cytogenomics, including karyotyping, FISH, chromosomal microarrays, and optical genome mapping, has yielded significant results for clinical phenotypes in constitutional and cancer genetics, including intellectual disability, autism spectrum disorders, dysmorphic features, and hematological and solid-tissue neoplasia. However, some of these assays have yielded results of unclear significance because the abnormalities detected were often located in intergenic regions of the genome. Because these abnormalities are within the \u201cdark matter\u201d of the genome, their clinical significance has been a matter of speculation. However, functional genomics can explore the clinical implications of such abnormalities more robustly, whether the abnormalities disrupt topologically associating domains (TADs), delete regulatory regions, etc. Some human genetic diseases associated with these intergenic abnormalities and characterized by functional genomics include preaxial polydactyly (SHH gene), Pierre Robin syndrome (SOX9), and 5q14.3 microdeletion syndrome (MEF2C). While functional genomics is a broad research topic, this review focuses on prior and current efforts to leverage functional genomics within the intergenic regions for human health.<\/jats:p>","DOI":"10.3390\/genes17070763","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"763","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Advances in Functional Genomics for Human Health"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1594-0233","authenticated-orcid":false,"given":"Patrick R.","family":"Gonzales","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/ng1416","article-title":"Detection of Large-Scale Variation in the Human Genome","volume":"36","author":"Iafrate","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrg1767","article-title":"Structural Variation in the Human Genome","volume":"7","author":"Feuk","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nature05329","article-title":"Global Variation in Copy Number in the Human Genome","volume":"444","author":"Redon","year":"2006","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1146\/annurev-med-100708-204735","article-title":"Structural Variation in the Human Genome and Its Role in Disease","volume":"61","author":"Stankiewicz","year":"2010","journal-title":"Annu. Rev. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41576-018-0003-4","article-title":"Piercing the Dark Matter: Bioinformatics of Long-Range Sequencing and Mapping","volume":"19","author":"Sedlazeck","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/nsmb.2784","article-title":"Enhancer Biology and Enhanceropathies","volume":"21","author":"Smith","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7548","DOI":"10.1073\/pnas.112212199","article-title":"Disruption of a Long-Range Cis-Acting Regulator for Shh Causes Preaxial Polydactyly","volume":"99","author":"Lettice","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/ng.329","article-title":"Highly Conserved Non-Coding Elements on Either Side of SOX9 Associated with Pierre Robin Sequence","volume":"41","author":"Benko","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/ng.3720","article-title":"The Genomic Landscape of Balanced Cytogenetic Abnormalities Associated with Human Congenital Anomalies","volume":"49","author":"Redin","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"ENCODE Project Consortium (2004). The ENCODE (ENCyclopedia of DNA Elements) Project. Science, 306, 636\u2013640.","DOI":"10.1126\/science.1105136"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"ENCODE Project Consortium (2012). An Integrated Encyclopedia of DNA Elements in the Human Genome. Nature, 489, 57\u201374.","DOI":"10.1038\/nature11247"},{"key":"ref_12","unstructured":"GTEx Consortium (2013). The Genotype-Tissue Expression (GTEx) Project. Nat. Genet., 45, 580\u2013585."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"GTEx Consortium (2020). The GTEx Consortium Atlas of Genetic Regulatory Effects across Human Tissues. Science, 18, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1101\/gr.190983.115","article-title":"Functional Genomics Bridges the Gap between Quantitative Genetics and Molecular Biology","volume":"25","author":"Lappalainen","year":"2015","journal-title":"Genome Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Federico, C., Brancato, D., Bruno, F., Coniglio, E., Sturiale, V., and Saccone, S. (2025). Cytogenetics and Cytogenomics in Clinical Diagnostics: Genome Architecture, Structural Variants, and Translational Applications. Genes, 16.","DOI":"10.3390\/genes16070780"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1126\/science.1098119","article-title":"Ultraconserved Elements in the Human Genome","volume":"304","author":"Bejerano","year":"2004","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1093\/molbev\/msm268","article-title":"Large-Scale Appearance of Ultraconserved Elements in Tetrapod Genomes and Slowdown of the Molecular Clock","volume":"25","author":"Stephen","year":"2008","journal-title":"Mol. Biol. Evol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature05295","article-title":"In Vivo Enhancer Analysis of Human Conserved Non-Coding Sequences","volume":"444","author":"Pennacchio","year":"2006","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1126\/science.1181369","article-title":"Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome","volume":"326","author":"Williams","year":"2009","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature11082","article-title":"Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions","volume":"485","author":"Dixon","year":"2012","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/bies.201200178","article-title":"Structural Variations, the Regulatory Landscape of the Genome and Their Alteration in Human Disease","volume":"35","author":"Spielmann","year":"2013","journal-title":"BioEssays"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.ajhg.2021.01.001","article-title":"Topologically Associating Domain Boundaries That Are Stable across Diverse Cell Types Are Evolutionarily Constrained and Enriched for Heritability","volume":"108","author":"McArthur","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.celrep.2015.01.016","article-title":"Deletions, Inversions, Duplications: Engineering of Structural Variants Using CRISPR\/Cas in Mice","volume":"10","author":"Kraft","year":"2015","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.cell.2015.04.004","article-title":"Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions","volume":"161","author":"Kraft","year":"2015","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s42003-023-04819-w","article-title":"Topologically Associating Domain Boundaries Are Required for Normal Genome Function","volume":"6","author":"Rajderkar","year":"2023","journal-title":"Commun. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The Zebrafish Reference Genome Sequence and Its Relationship to the Human Genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Morice, E., Calhoun, C., Lalonde, R., and Leask, M. (2023). Zebrafish for the Study of Enhancer Activity in Human Traits and Disease. Zebrafish Research\u2014An Ever-Expanding Experimental Model, IntechOpen.","DOI":"10.5772\/intechopen.1003949"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s00427-013-0453-9","article-title":"Functional Analysis of Limb Enhancers in the Developing Fin","volume":"223","author":"Booker","year":"2013","journal-title":"Dev. Genes Evol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"eaaw1668","DOI":"10.1126\/sciadv.aaw1668","article-title":"Principles of Genome Folding into Topologically Associating Domains","volume":"5","author":"Szabo","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Krefting, J., Andrade-Navarro, M.A., and Ibn-Salem, J. (2018). Evolutionary Stability of Topologically Associating Domains Is Associated with Conserved Gene Regulation. BMC Biol., 16.","DOI":"10.1186\/s12915-018-0556-x"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e21856","DOI":"10.7554\/eLife.21856","article-title":"An Efficient Targeted Nuclease Strategy for High-Resolution Mapping of DNA Binding Sites","volume":"6","author":"Skene","year":"2017","journal-title":"Elife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.cell.2018.03.016","article-title":"Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Holt, L.M., Chen, E.P., Hughes, B.W., and Nestler, E.J. (2025). CUT&RUN as a Powerful Tool for Chromatin Profiling: A Focus on Neuropsychiatric Disorders. Biol. Psychiatry, 1\u20138.","DOI":"10.1016\/j.biopsych.2025.08.012"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.ajhg.2020.04.016","article-title":"Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases","volume":"106","author":"Melo","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41431-026-02086-x","article-title":"Non-Coding Structural Variants Disrupting Conserved PITX2 Enhancer Loci in Axenfeld\u2013Rieger Syndrome","volume":"34","author":"Mitchell","year":"2026","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_36","first-page":"1","article-title":"Enhancer Hijacking at the ARHGAP36 Locus Is Associated with Connective Tissue to Bone Transformation","volume":"14","author":"Melo","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Gonzales, P.R. (2025). Integration of Newer Genomic Technologies into Clinical Cytogenetics Laboratories. Genes, 16.","DOI":"10.3390\/genes16060688"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nrg2641","article-title":"Applications of Next-Generation Sequencing: ChIP\u2013Seq: Advantages and Challenges of a Maturing Technology","volume":"10","author":"Park","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1158\/0008-5472.CAN-22-2682","article-title":"Spatial Transcriptomic Analysis of a Diverse Patient Cohort Reveals a Conserved Architecture in Triple-Negative Breast Cancer","volume":"83","author":"Bassiouni","year":"2023","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1101\/gr.279105.124","article-title":"Single-Nucleus CUT&RUN Elucidates the Function of Intrinsic and Genomics-Driven Epigenetic Heterogeneity in Head and Neck Cancer Progression","volume":"35","author":"Womersley","year":"2025","journal-title":"Genome Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102745","DOI":"10.1016\/j.bcmd.2023.102745","article-title":"High-Throughput Methods for the Analysis of Transcription Factors and Chromatin Modifications: Low Input, Single Cell and Spatial Genomic Technologies","volume":"101","author":"Salma","year":"2023","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41586-024-07510-0","article-title":"Deciphering the Impact of Genomic Variation on Function","volume":"633","author":"Samer","year":"2024","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41392-023-01309-7","article-title":"CRISPR\/Cas9 Therapeutics: Progress and Prospects","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/763\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:48:56Z","timestamp":1782877736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/763"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["genes17070763"],"URL":"https:\/\/doi.org\/10.3390\/genes17070763","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}