{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:29:09Z","timestamp":1785403749028,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science, Technological Development, and Innovation","award":["451-03-34\/2026-03\/200111"],"award-info":[{"award-number":["451-03-34\/2026-03\/200111"]}]},{"award":["451-03-34\/2026-03\/200111"],"award-info":[{"award-number":["451-03-34\/2026-03\/200111"]}],"id":[{"id":"https:\/\/ror.org\/01znas443","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010301","name":"Faculty of Medical Sciences, University of Kragujevac","doi-asserted-by":"publisher","award":["05\/20"],"award-info":[{"award-number":["05\/20"]}],"id":[{"id":"10.13039\/501100010301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010301","name":"Faculty of Medical Sciences, University of Kragujevac","doi-asserted-by":"publisher","award":["22\/2025"],"award-info":[{"award-number":["22\/2025"]}],"id":[{"id":"10.13039\/501100010301","id-type":"DOI","asserted-by":"publisher"}]},{"award":["05\/20"],"award-info":[{"award-number":["05\/20"]}],"id":[{"id":"https:\/\/ror.org\/04f7vj627","id-type":"ROR","asserted-by":"publisher"}]},{"award":["22\/2025"],"award-info":[{"award-number":["22\/2025"]}],"id":[{"id":"https:\/\/ror.org\/04f7vj627","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The neurexin1 gene (NRXN1) encodes a presynaptic adhesion molecule that plays a critical role in synapse formation, maintenance, and function. Copy-number variants (CNVs) affecting the NRXN1 locus, including submicroscopic deletions, represent rare variant acting as a predisposition for neurodevelopmental disorders, such as Pitt\u2013Hopkins-like syndrome type 2 (MIM #614325) and susceptibility to schizophrenia (MIM #621407). Variations in NRXN1 gene are associated with marked clinical heterogeneity. We present a familial case involving two male siblings (aged 6 and 5 years) and their 28-year-old mother, all exhibiting variable neurodevelopmental phenotypes. Both children demonstrated disharmonic developmental profiles characterized by impaired communication, speech largely intelligible only to their parents, and behaviors consistent with autism spectrum disorder, including reduced eye contact. Mother represents a carrier with only subtle, nonspecific behavioral traits, further supporting the concept of incomplete penetrance and variable expressivity associated with this genetic alteration. Genetic analysis identified a 317 kb NRXN1 deletion shared by all affected family members, accompanied by significant intrafamilial phenotypic variability, suggesting the contribution of additional genetic and\/or modifying factors. These findings support the concept that NRXN1 deletions alone do not determine clinical outcome but rather act within a broader genetic and biological context. The marked intrafamilial phenotypic variability and incomplete penetrance observed in this family is compatible with a multiple-hit model, whereby NRXN1 deletions act as susceptibility factors whose phenotypic consequences are shaped by additional genetic and modifying influences. However, the genetic mechanisms underlying the observed phenotypic variability warrant further investigation.<\/jats:p>","DOI":"10.3390\/ijms27146241","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:34:44Z","timestamp":1783996484000},"page":"6241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intrafamilial Variability in NRXN1-Associated Neurodevelopmental Disorders: Clinical and Genetic Insights from a Family Case Study with Literature Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-7414","authenticated-orcid":false,"given":"Nikolina","family":"Kastratovic","sequence":"first","affiliation":[{"name":"Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-9004","authenticated-orcid":false,"given":"Marina","family":"Gazdic Jankovic","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5177-1521","authenticated-orcid":false,"given":"Marina","family":"Miletic Kovacevic","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Nikolic","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7474-7495","authenticated-orcid":false,"given":"Dragica","family":"Pavlovic","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1077-2373","authenticated-orcid":false,"given":"Dijana","family":"Perovic","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6072-085X","authenticated-orcid":false,"given":"Vladimir","family":"Janjic","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia"},{"name":"Psychiatry Clinic, University Clinical Center Kragujevac, Zmaj Jovina 30, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6759-2720","authenticated-orcid":false,"given":"Biljana","family":"Ljujic","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Friedman, A.E., Perni, M., Millard, J., Karanfilovski, D., Granato, M., and Campbell, P.D. (2026). Unique and overlapping behavioral effects of isoform-specific NRXN1 deletions across development. bioRxiv.","DOI":"10.64898\/2026.01.22.698702"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.neuron.2014.09.011","article-title":"Targeted combinatorial alternative splicing generates brain region-specific repertoires of neurexins","volume":"84","author":"Schreiner","year":"2014","journal-title":"Neuron"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sciacca, M., Marino, L., Vitaliti, G., Falsaperla, R., and Marino, S. (2022). NRXN1 Deletion in Two Twins\u2019 Genotype and Phenotype: A Clinical Case and Literature Review. Children, 9.","DOI":"10.3390\/children9050698"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Smisko, W.R., Haury, W.R., Perni, M., Kalik, R., Palo, J., Bastien, B.L., Bilchak, J.N., Jongens, T.A., Kayser, M.S., and Hart, M.P. (2026). Allele-specific rescue of neurexin behavioral phenotypes by monoamine-targeting compounds. bioRxiv.","DOI":"10.64898\/2026.02.06.703315"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/cge.13537","article-title":"Phenotypic spectrum of NRXN1 mono- and bi-allelic deficiency: A systematic review","volume":"97","author":"Castronovo","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20240979","DOI":"10.1515\/med-2024-0979","article-title":"NRXN1-related disorders, attempt to better define clinical assessment","volume":"19","author":"Pavone","year":"2024","journal-title":"Open Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17998","DOI":"10.1073\/pnas.0910297106","article-title":"Mouse neurexin-1\u03b1 deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments","volume":"106","author":"Etherton","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/ajmg.b.31063","article-title":"Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders","volume":"153B","author":"Ching","year":"2010","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/mgg3.105","article-title":"A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion","volume":"2","author":"Gabau","year":"2014","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1038\/s41467-023-39420-6","article-title":"Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids","volume":"14","author":"Sebastian","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_11","first-page":"103591","article-title":"NRXN1 deletion syndrome: Phenotypic spectrum and penetrance","volume":"62","author":"Forman","year":"2019","journal-title":"Eur. J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1002\/ajmg.b.32148","article-title":"Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature","volume":"162","author":"Bruno","year":"2013","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1038\/s41588-019-0539-z","article-title":"Neuronal impact of patient-specific aberrant NRXN1\u03b1 splicing","volume":"51","author":"Flaherty","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/gim.2016.54","article-title":"Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression","volume":"19","author":"Lowther","year":"2017","journal-title":"Genet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neulet.2006.08.017","article-title":"High frequency of neurexin 1beta signal peptide structural variants in patients with autism","volume":"409","author":"Feng","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41583-020-00415-7","article-title":"Neurexins: Molecular codes for shaping neuronal synapses","volume":"22","author":"Gomez","year":"2021","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.cell.2017.10.024","article-title":"Synaptic neurexin complexes: A molecular code for the logic of neural circuits","volume":"171","year":"2017","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41525-024-00450-8","article-title":"Analysis of exonic deletions in a large population study identifies NRXN1 as a hotspot for non-recurrent copy number variants","volume":"9","author":"Montalbano","year":"2024","journal-title":"npj Genom. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cooper, J.N., Mittal, J., Sangadi, A., Klassen, D.L., King, A.M., Zalta, M., Mittal, R., and Eshraghi, A.A. (2024). Landscape of NRXN1 gene variants in phenotypic manifestations of autism spectrum disorder: A systematic review. J. Clin. Med., 13.","DOI":"10.3390\/jcm13072067"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.neures.2017.10.012","article-title":"Neurexins and neuropsychiatric disorders","volume":"127","author":"Kasem","year":"2018","journal-title":"Neurosci. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1002\/ajmg.a.34255","article-title":"Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters","volume":"155","author":"Harrison","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"107141","DOI":"10.1016\/j.clineuro.2022.107141","article-title":"Homozygous exonic and intragenic NRXN1 deletion presenting as either West syndrome or autism spectrum disorder in two siblings","volume":"214","author":"Ayaz","year":"2022","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1136\/jmg.2007.054437","article-title":"A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha","volume":"45","author":"Zahir","year":"2008","journal-title":"J. Med. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1038\/ejhg.2012.95","article-title":"Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions","volume":"20","author":"Schaaf","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/ajmg.a.35780","article-title":"Investigation of NRXN1 deletions: Clinical and molecular characterization","volume":"161","author":"Dabell","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/gb-2013-14-9-213","article-title":"Neurexins","volume":"14","author":"Reissner","year":"2013","journal-title":"Genome Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s00439-023-02552-2","article-title":"Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder","volume":"142","author":"Accogli","year":"2023","journal-title":"Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/ajmg.b.32036","article-title":"Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders","volume":"159B","author":"Duong","year":"2012","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/ajmg.b.32673","article-title":"A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three-generation Chinese family","volume":"177","author":"Yuan","year":"2018","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"ref_31","first-page":"1361","article-title":"Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and evidence for a multiple-hit model of autism","volume":"20","author":"Gauthier","year":"2011","journal-title":"Hum. Mol. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6241\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T04:27:39Z","timestamp":1784176059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6241"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":31,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146241"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146241","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}