{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n A growing body of evidence implicates the CNTNAP2 gene—which encodes the CASPR2 protein, a member of the neurexin superfamily—in the regulation of key neurodevelopmental processes such as neuronal migration, synapse formation, and network connectivity. Studies using CNTNAP2‐deficient mouse models demonstrate that loss of this gene leads to deficits in social behavior, communication, and repetitive behaviors, in addition to hyperactivity and epilepsy, consistent with core features of autism spectrum disorders (ASD)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Human genetic studies further show that common polymorphisms in CNTNAP2 are associated with ASD and language impairments, with notable effects on frontal lobe connectivity and a pronounced male and parent‐of‐origin bias."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " In addition, alterations in CNTNAP2—whether through genomic rearrangements, deletions, or mutations—have been linked not only to epilepsy and schizophrenia but also to neurodevelopmental syndromes that include disrupted language acquisition and cognitive deficits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " At the mechanistic level, CNTNAP2 is subject to transcriptional regulation by FOXP2, a transcription factor critical for speech and language, thereby providing a molecular bridge between genetic risk factors for specific language impairment and ASD."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, association studies in early childhood indicate that common variants in CNTNAP2 also influence early language acquisition in the general population"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", while comprehensive reviews underscore its broad role in modulating synaptic connectivity and neuronal circuit assembly across neuropsychiatric conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these studies suggest that proper CNTNAP2 function is essential for the establishment and maintenance of neural networks underlying language, cognition, and behavioral regulation, and that its disruption contributes to a spectrum of neurodevelopmental and neuropsychiatric disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Olga Peñagarikano, Brett S Abrahams, Edward I Herman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2011.08.040"}], "href": "https://doi.org/10.1016/j.cell.2011.08.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21962519"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21962519"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kevin A Strauss, Erik G Puffenberger, Matthew J Huentelman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa052773"}], "href": "https://doi.org/10.1056/NEJMoa052773"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16571880"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16571880"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Maricela Alarcón, Brett S Abrahams, Jennifer L Stone, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2007.09.005"}], "href": "https://doi.org/10.1016/j.ajhg.2007.09.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18179893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18179893"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Dan E Arking, David J Cutler, Camille W Brune, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2007.09.015"}], "href": "https://doi.org/10.1016/j.ajhg.2007.09.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18179894"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18179894"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ashley A Scott-Van Zeeland, Brett S Abrahams, Ana I Alvarez-Retuerto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.3001344"}], "href": "https://doi.org/10.1126/scitranslmed.3001344"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21048216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21048216"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "J I Friedman, T Vrijenhoek, S Markx, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.mp.4002049"}], "href": "https://doi.org/10.1038/sj.mp.4002049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17646849"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17646849"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Annemieke J M H Verkerk, Carol A Mathews, Marijke Joosse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0888-7543(03)00097-1"}], "href": "https://doi.org/10.1016/s0888-7543(03"}, {"type": "t", "text": "00097-1) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12809671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12809671"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sonja C Vernes, Dianne F Newbury, Brett S Abrahams, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A functional genetic link between distinct developmental language disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa0802828"}], "href": "https://doi.org/10.1056/NEJMoa0802828"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18987363"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18987363"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "A J O Whitehouse, D V M Bishop, Q W Ang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CNTNAP2 variants affect early language development in the general population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Brain Behav (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1601-183X.2011.00684.x"}], "href": "https://doi.org/10.1111/j.1601-183X.2011.00684.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21310003"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21310003"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Pedro Rodenas-Cuadrado, Joses Ho, Sonja C Vernes "}, {"type": "b", "children": [{"type": "t", "text": "Shining a light on CNTNAP2: complex functions to complex disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2013.100"}], "href": "https://doi.org/10.1038/ejhg.2013.100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23714751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23714751"}]}]}]}