{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T04:28:55Z","timestamp":1782534535231,"version":"3.54.5"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2019,7,15]],"date-time":"2019-07-15T00:00:00Z","timestamp":1563148800000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["5U01MH101723-02"],"award-info":[{"award-number":["5U01MH101723-02"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004040","name":"KU Leuven","doi-asserted-by":"publisher","award":["C14\/18\/092"],"award-info":[{"award-number":["C14\/18\/092"]}],"id":[{"id":"10.13039\/501100004040","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["GOE1117N"],"award-info":[{"award-number":["GOE1117N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001673","name":"Fondation J\u00e9r\u00f4me Lejeune","doi-asserted-by":"publisher","award":["1665"],"award-info":[{"award-number":["1665"]}],"id":[{"id":"10.13039\/501100001673","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The majority (99%) of individuals with 22q11.2 deletion syndrome (22q11.2DS) have a deletion that is caused by non-allelic homologous recombination between two of four low copy repeat clusters on chromosome 22q11.2 (LCR22s). However, in a small subset of patients, atypical deletions are observed with at least one deletion breakpoint within unique sequence between the LCR22s. The position of the chromosome breakpoints and the mechanisms driving those atypical deletions remain poorly studied. Our large-scale, whole genome sequencing study of &amp;gt;1500 subjects with 22q11.2DS identified six unrelated individuals with atypical deletions of different types. Using a combination of whole genome sequencing data and fiber-fluorescence in situ hybridization, we mapped the rearranged alleles in these subjects. In four of them, the distal breakpoints mapped within one of the LCR22s and we found that the deletions likely occurred by replication-based mechanisms. Interestingly, in two of them, an inversion probably preceded inter-chromosomal \u2018allelic\u2019 homologous recombination between differently oriented LCR22-D alleles. Inversion associated allelic homologous recombination (AHR) may well be a common mechanism driving (atypical) deletions on 22q11.2.<\/jats:p>","DOI":"10.1093\/hmg\/ddz166","type":"journal-article","created":{"date-parts":[[2019,7,10]],"date-time":"2019-07-10T15:10:55Z","timestamp":1562771455000},"page":"3724-3733","source":"Crossref","is-referenced-by-count":10,"title":["Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0805-8149","authenticated-orcid":false,"given":"Lisanne","family":"Vervoort","sequence":"first","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram","family":"Demaerel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Y","family":"Rengifo","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Odrzywolski","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"},{"name":"Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elfi","family":"Vergaelen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S","family":"Hestand","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"},{"name":"Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, USA"},{"name":"Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Breckpot","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Devriendt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Swillen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna M","family":"McDonald-McGinn","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ania M","family":"Fiksinski","sequence":"additional","affiliation":[{"name":"Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"The Dalglish Family 22q Clinic and Centre for Addiction and Mental Health, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janneke R","family":"Zinkstok","sequence":"additional","affiliation":[{"name":"Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernice E","family":"Morrow","sequence":"additional","affiliation":[{"name":"Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Heung","sequence":"additional","affiliation":[{"name":"The Dalglish Family 22q Clinic and Centre for Addiction and Mental Health, Toronto, ON, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob A S","family":"Vorstman","sequence":"additional","affiliation":[{"name":"Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands"},{"name":"The Dalglish Family 22q Clinic and Centre for Addiction and Mental Health, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne S","family":"Bassett","sequence":"additional","affiliation":[{"name":"The Dalglish Family 22q Clinic and Centre for Addiction and Mental Health, Toronto, ON, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva W C","family":"Chow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"name":"Clinical Genetics Service, Centre for Addiction and Mental Health, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Shashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"International 22q11.2 Brain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Behavior Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joris R","family":"Vermeesch","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,7,13]]},"reference":[{"key":"2019122822374047700_ref1","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1136\/jmg.35.9.789-a","article-title":"The annual incidence of DiGeorge\/velocardiofacial syndrome","volume":"35","author":"Devriendt","year":"1998","journal-title":"J. Med. Genet."},{"key":"2019122822374047700_ref2","first-page":"1","article-title":"22q11.2 deletion syndrome","volume":"1","author":"McDonald-McGinn","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"2019122822374047700_ref3","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s11920-008-0026-1","article-title":"Schizophrenia and 22q11.2 deletion syndrome","volume":"10","author":"Bassett","year":"2008","journal-title":"Curr. Psychiatry Rep."},{"key":"2019122822374047700_ref4","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1176\/appi.ajp.2013.13070864","article-title":"Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome results from the international","volume":"171","author":"Schneider","year":"2014","journal-title":"Am. J. Psychiatry"},{"key":"2019122822374047700_ref5","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1002\/ajmg.c.31435","article-title":"Developmental trajectories in 22q11.2 deletion syndrome","volume":"169","author":"Swillen","year":"2015","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"2019122822374047700_ref6","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1002\/ajmg.a.40387","article-title":"Understanding the pediatric psychiatric phenotype of 22q11.2 deletion syndrome","volume":"176","author":"Fiksinski","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"2019122822374047700_ref7","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1101\/gr.GR-1871R","article-title":"Segmental duplications: organization and impact within the current human genome project assembly","volume":"11","author":"Bailey","year":"2001","journal-title":"Genome Res."},{"key":"2019122822374047700_ref8","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1126\/science.1072047","article-title":"Recent segmental duplications in the human genome","volume":"297","author":"Bailey","year":"2002","journal-title":"Science"},{"key":"2019122822374047700_ref9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1471-2164-12-71","article-title":"Characterization of the past and current duplication activities in the human 22q11.2 region","volume":"12","author":"Guo","year":"2011","journal-title":"BMC Genomics"},{"key":"2019122822374047700_ref10","doi-asserted-by":"crossref","first-page":"R57","DOI":"10.1093\/hmg\/ddh073","article-title":"Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease","volume":"13 Spec","author":"Shaw","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2019122822374047700_ref11","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1755-8417-1-4","article-title":"Mechanisms for human genomic rearrangements","volume":"1","author":"Gu","year":"2008","journal-title":"Pathogenetics"},{"key":"2019122822374047700_ref12","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":"2019122822374047700_ref13","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1093\/hmg\/ddy028","article-title":"Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2","volume":"27","author":"Guo","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"2019122822374047700_ref14","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ejmg.2009.02.008","article-title":"Microduplication 22q11.2: a new chromosomal syndrome","volume":"52","author":"Portno\u00ef","year":"2009","journal-title":"Eur. J. Med. Genet."},{"key":"2019122822374047700_ref15","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.ejmg.2009.05.010","article-title":"Atypical deletion of 22q11.2: detection using the FISH TBX1 probe and molecular characterization with high-density SNP arrays","volume":"52","author":"Beaujard","year":"2009","journal-title":"Eur. J. Med. Genet."},{"key":"2019122822374047700_ref16","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/sj.ejhg.5200399","article-title":"Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge\/velo-cardio-facial syndrome","volume":"7","author":"Amati","year":"1999","journal-title":"Eur. J. Hum. Genet."},{"key":"2019122822374047700_ref17","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1007\/s00439-006-0242-x","article-title":"Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome","volume":"120","author":"Weksberg","year":"2007","journal-title":"Hum. Genet."},{"key":"2019122822374047700_ref18","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1086\/515508","article-title":"Molecular definition of 22q11 deletions in 151 Velo-cardio-facial syndrome patients","volume":"61","author":"Carlson","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"2019122822374047700_ref19","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1093\/hmg\/4.12.2417","article-title":"Interstitial 22q11 microdeletion excluding the ADU breakpoint in a patient with DiGeorge syndrome","volume":"4","author":"Levy","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"2019122822374047700_ref20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/(SICI)1096-8628(19990903)86:1<27::AID-AJMG6>3.0.CO;2-7","article-title":"Patient with a 22q11.2 deletion with no overlap of the minimal DiGeorge syndrome critical region (MDGCR)","volume":"86","author":"McQuade","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"2019122822374047700_ref21","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.ejmg.2008.02.001","article-title":"Atypical 22q11.2 deletion in a patient with DGS\/VCFS spectrum","volume":"51","author":"Nogueira","year":"2008","journal-title":"Eur. J. Med. Genet."},{"key":"2019122822374047700_ref22","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1086\/523992","article-title":"Detection of an atypical 22q11 deletion that has no overlap with the DiGeorge syndrome critical region","volume":"60","author":"O\u2019Donnell","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"2019122822374047700_ref23","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/hmg\/9.4.489","article-title":"Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis","volume":"9","author":"Shaikh","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"2019122822374047700_ref24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/1471-2350-7-18","article-title":"Breakpoint associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions","volume":"7","author":"Uddin","year":"2006","journal-title":"BMC Med. Genet."},{"key":"2019122822374047700_ref25","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1038\/mp.2017.161","article-title":"A neurogenetic model for the study of schizophrenia spectrum disorders: the international 22q11.2 deletion syndrome brain behavior consortium","volume":"22","author":"Gur","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"2019122822374047700_ref26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"2019122822374047700_ref27","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1101\/gr.229202","article-title":"BLAT\u2014the BLAST-like alignment tool","volume":"12","author":"Kent","year":"2002","journal-title":"Genome Res."},{"key":"2019122822374047700_ref28","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.ygeno.2018.03.012","article-title":"A simple and novel DNA combing methodology for fiber-FISH and optical mapping","volume":"111","author":"Yadav","year":"2019","journal-title":"Genomics"},{"key":"2019122822374047700_ref29","doi-asserted-by":"crossref","DOI":"10.1101\/403873","article-title":"The 22q11 low copy repeats are characterized by unprecedented size and structure variability","volume-title":"Genome Res.","author":"Demaerel"},{"key":"2019122822374047700_ref30","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1002\/ajmg.a.40637","article-title":"What is new with 22q? An update from the 22q and you Center at the Children\u2019s Hospital of Philadelphia","volume":"176A","author":"Campbell","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"2019122822374047700_ref31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/jcp.25053","article-title":"Error-prone repair of DNA double-strand breaks","volume":"231","author":"Rodgers","year":"2016","journal-title":"J. Cell. Physiol."},{"key":"2019122822374047700_ref32","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.tig.2014.01.001","article-title":"The role of microhomology in genomic structural variation","volume":"30","author":"Ottaviani","year":"2014","journal-title":"Trends Genet."},{"key":"2019122822374047700_ref33","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1093\/hmg\/ddp151","article-title":"Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching","volume":"18","author":"Carvalho","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2019122822374047700_ref34","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1016\/j.cell.2019.01.045","article-title":"Megabase length hypermutation accompanies article megabase length hypermutation accompanies","volume":"176","author":"Beck","year":"2019","journal-title":"Cell"},{"key":"2019122822374047700_ref35","doi-asserted-by":"crossref","first-page":"e1002371","DOI":"10.1371\/journal.pgen.1002371","article-title":"The NF1 gene contains hotspots for L1 endonuclease-dependent De novo insertion","volume":"7","author":"Wimmer","year":"2011","journal-title":"PLoS Genet."},{"key":"2019122822374047700_ref36","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1038\/ng.2768","article-title":"Replicative mechanisms for CNV formation are error prone","volume":"45","author":"Carvalho","year":"2013","journal-title":"Nat. Genet."},{"key":"2019122822374047700_ref37","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/ng753","article-title":"A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome","volume":"29","author":"Osborne","year":"2001","journal-title":"Nat. Genet."},{"key":"2019122822374047700_ref38","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1093\/hmg\/ddg101","article-title":"Genomic inversions of human chromosome 15q11-q13 in mothers of Angelman syndrome patients with class II (BP2\/3) deletions","volume":"12","author":"Gimelli","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2019122822374047700_ref39","doi-asserted-by":"crossref","first-page":"829825","DOI":"10.5402\/2011\/829825","article-title":"22q13.32 deletion and duplication and inversion in the same family: a rare occurrence","volume":"2011","author":"Jafri","year":"2011","journal-title":"ISRN Pediatr."},{"key":"2019122822374047700_ref40","article-title":"Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM","author":"Li","year":"2013"},{"key":"2019122822374047700_ref41","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/bioinformatics\/btq635","article-title":"Control-free calling of copy number alterations in deep-sequencing data using GC-content normalization","volume":"27","author":"Boeva","year":"2011","journal-title":"Bioinformatics"},{"key":"2019122822374047700_ref42","doi-asserted-by":"crossref","DOI":"10.1007\/978-0-387-98141-3","volume-title":"ggplot2: Elegant Graphics for Data Analysis 1st ed","author":"Wickham","year":"2009"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/22\/3724\/31630981\/ddz166.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/22\/3724\/31630981\/ddz166.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,12,28]],"date-time":"2019-12-28T22:38:01Z","timestamp":1577572681000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/28\/22\/3724\/5531819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,13]]},"references-count":42,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2019,7,13]]},"published-print":{"date-parts":[[2019,11,15]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddz166","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,11,15]]},"published":{"date-parts":[[2019,7,13]]}}}