{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T22:15:03Z","timestamp":1771884903856,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"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>22q11.2 is a region prone to chromosomal rearrangements due to the presence of eight large blocks of low-copy repeats (LCR22s). The 3 Mb 22q11.2 \u201ctypical deletion\u201d, between LCR22-A and D, causes a fairly well-known clinical picture, while the effects of smaller CNVs harbored in this interval are still to be fully elucidated. Nested deletions, flanked by LCR22B-D, LCR22B-C, or LCR22C-D, are very rare and are collectively described as \u201ccentral deletions\u201d. The LCR22C-D deletion (CDdel) has never been separately analyzed. In this paper, we focused only on CDdel, evaluating its gene content and reviewing the literature and public databases in order to obtain new insights for the classification of this CNV. At first glance, CDdels are associated with a broad phenotypic spectrum, ranging from clinically normal to quite severe phenotypes. However, the frequency of specific clinical traits highlights that renal\/urinary tract abnormalities, cardiac defects, and neurological\/behavioral disorders are much more common in CDdel than in the general population. This frequency is too high to be fortuitous, indicating that CDdel is a predisposing factor for these phenotypic traits. Among the genes present in this interval, CRKL is an excellent candidate for cardiac and renal defects. Even if further data are necessary to confirm the role of CDdels, according to our review, this CNV fits into the class of \u2018likely pathogenic\u2019 CNVs.<\/jats:p>","DOI":"10.3390\/genes16010072","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T11:29:37Z","timestamp":1736422177000},"page":"72","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["22q11.21 Deletions: A Review on the Interval Mediated by Low-Copy Repeats C and D"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6479-7459","authenticated-orcid":false,"given":"Veronica","family":"Bertini","sequence":"first","affiliation":[{"name":"Section of Cytogenetics, Oncology Department, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Cambi","sequence":"additional","affiliation":[{"name":"Section of Cytogenetics, Oncology Department, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Legitimo","sequence":"additional","affiliation":[{"name":"Section of Clinical and Laboratory Immunology, Pediatric Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-3727","authenticated-orcid":false,"given":"Giorgio","family":"Costagliola","sequence":"additional","affiliation":[{"name":"Section of Pediatric Hematology and Oncology, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-1945","authenticated-orcid":false,"given":"Rita","family":"Consolini","sequence":"additional","affiliation":[{"name":"Section of Clinical and Laboratory Immunology, Pediatric Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Valetto","sequence":"additional","affiliation":[{"name":"Section of Cytogenetics, Oncology Department, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","unstructured":"Vervoort, L., and Vermeesch, J.R. (2022). The 22q11.2 Low Copy Repeats. Genes, 13.","DOI":"10.3390\/genes13112101"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Szczawi\u0144ska-Pop\u0142onyk, A., Schwartzmann, E., Chmara, Z., G\u0142ukowska, A., Krysa, T., Majchrzycki, M., Olejnicki, M., Ostrowska, P., and Babik, J. (2023). Chromosome 22q11.2 Deletion Syndrome: A Comprehensive Review of Molecular Genetics in the Context of Multidisciplinary Clinical Approach. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202304.0652.v1"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bertini, V., Azzar\u00e0, A., Legitimo, A., Milone, R., Battini, R., Consolini, R., and Valetto, A. (2017). Deletion Extents Are Not the Cause of Clinical Variability in 22q11.2 Deletion Syndrome: Does the Interaction between DGCR8 and miRNA-CNVs Play a Major Role?. Front. Genet., 8.","DOI":"10.3389\/fgene.2017.00047"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1126\/science.aap7607","article-title":"Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination","volume":"362","author":"Steklov","year":"2018","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1093\/hmg\/ddy412","article-title":"Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling","volume":"28","author":"Motta","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/85855","article-title":"Mice lacking the homologue of the human 22q11. 2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome","volume":"27","author":"Guris","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ajhg.2014.12.025","article-title":"Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation","volume":"96","author":"Racedo","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1056\/NEJMoa1609009","article-title":"Genetic Drivers of Kidney Defects in the DiGeorge Syndrome","volume":"376","author":"Liu","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ajhg.2019.11.010","article-title":"Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects","volume":"106","author":"Zhao","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102208","DOI":"10.1016\/j.gde.2024.102208","article-title":"Chromatin insulator mechanisms ensure accurate gene expression by controlling overall 3D genome organization","volume":"87","author":"Bhattacharya","year":"2024","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Rooney, K., Levy, M.A., Haghshenas, S., Kerkhof, J., Rogaia, D., Tedesco, M.G., Imperatore, V., Mencarelli, A., Squeo, G.M., and Di Venere, E. (2021). Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168611"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/humu.20640","article-title":"Detailed analysis of 22q11.2 with a high density MLPA probe set","volume":"29","author":"Jalali","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1755-8166-2-9","article-title":"A novel deletion in proximal 22q associated with cardiac septal defects and microcephaly: A case report","volume":"2","author":"Ogilvie","year":"2009","journal-title":"Mol. Cytogenet."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez, L., Nevado, J., Santos, F., Heine-Su\u00f1er, D., Martinez-Glez, V., Garc\u00eda-Mi\u00f1aur, S., Palomo, R., Delicado, A., Pajares, I.L., and Palomares, M. (2009). A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review. BMC Med. Genet., 10.","DOI":"10.1186\/1471-2350-10-48"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1002\/ajmg.a.35217","article-title":"Congenital heart defects in a novel recurrent 22q11.2 deletion harboring the genes CRKL and MAPK1","volume":"158A","author":"Breckpot","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1159\/000334262","article-title":"22q11.2 Distal Deletion Syndrome: Description of a New Case with Truncus Arteriosus Type 2 and Review","volume":"2","author":"Garavelli","year":"2011","journal-title":"Mol. Syndr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.1002\/ajmg.a.36177","article-title":"High-Resolution Analysis of Copy Number Variants in Adults with Simple-to-Moderate Congenital Heart Disease","volume":"161A","author":"Zhao","year":"2013","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1002\/ajmg.a.36711","article-title":"Central 22q11.2 deletions","volume":"164A","author":"Rump","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1159\/000438708","article-title":"22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features","volume":"146","author":"Burnside","year":"2015","journal-title":"Cytogenet. Genome Res."},{"key":"ref_21","first-page":"1377","article-title":"Deletion mapping of 22q11 in CATCH22 syndrome: Identification of a second critical region","volume":"58","author":"Kurahashi","year":"1996","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1002\/ajmg.a.31787","article-title":"An inherited atypical 1 Mb 22q11.2 deletion within the DGS\/VCFS 3 Mb region in a child with obesity and aggressive behavior","volume":"143A","author":"Jehee","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1159\/000330123","article-title":"Identification of Copy Number Variants on Human Chromosome 22 in Patients with a Variety of Clinical Findings","volume":"134","author":"Yu","year":"2011","journal-title":"Cytogenet. Genome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.ajhg.2012.10.007","article-title":"Copy-Number Disorders Are a Common Cause of Congenital Kidney Malformations","volume":"91","author":"Kiryluk","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1002\/ajmg.a.35517","article-title":"Phenotypic variability of atypical 22q11.2 deletions not including TBX1","volume":"158A","author":"Verhagen","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/ajmg.a.37408","article-title":"Cleft palate in a patient with the nested 22q11.2 LCR C to D deletion","volume":"170A","author":"Williams","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13229-017-0171-7","article-title":"Critical region within 22q11.2 linked to higher rate of autism spectrum disorder","volume":"8","author":"Clements","year":"2017","journal-title":"Mol. Autism"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gavril, E.C., Popescu, R., Nuc\u0103, I., Ciobanu, C.G., Butnariu, L.I., Rusu, C., and P\u00e2nzaru, M.C. (2022). Different Types of Deletions Created by Low-Copy Repeats Sequences Location in 22q11.2 Deletion Syndrome: Genotype-Phenotype Correlation. Genes, 13.","DOI":"10.3390\/genes13112083"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"187","DOI":"10.5507\/bp.2021.019","article-title":"MLPA analysis of 32 foetuses with a congenital heart defect and 1 foetus with renal defects\u2014Pilot study. The significant frequency rate of presented pathological CNV","volume":"166","author":"Stefekova","year":"2022","journal-title":"Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc Czech Repub."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1002\/ajmg.a.38662","article-title":"Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: From well-established knowledge to new frontiers","volume":"176","author":"Unolt","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/S0735-1097(02)01886-7","article-title":"The incidence of congenital heart disease","volume":"39","author":"Hoffman","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bertini, V., Milone, R., Cristofani, P., Cambi, F., Bosetti, C., Barbieri, F., Bertelloni, S., Cioni, G., Valetto, A., and Battini, R. (2022). Enhancing DLG2 Implications in Neuropsychiatric Disorders: Analysis of a Cohort of Eight Patients with 11q14.1 Imbalances. Genes, 12.","DOI":"10.3390\/genes13050859"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e00507","DOI":"10.1002\/mgg3.507","article-title":"Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance","volume":"7","author":"Woodwar","year":"2019","journal-title":"Mol. Genet. Genomic. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Costagliola, G., Legitimo, A., Bertini, V., Alberio, A.M.Q., Valetto, A., and Consolini, R. (2023). Distinct Immunophenotypic Features in Patients Affected by 22q11.2 Deletion Syndrome with Immune Dysregulation and Infectious Phenotype. J. Clin. Med., 12.","DOI":"10.3390\/jcm12247579"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/1\/72\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:26:02Z","timestamp":1759919162000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/1\/72"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,9]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["genes16010072"],"URL":"https:\/\/doi.org\/10.3390\/genes16010072","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,9]]}}}