{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:02:43Z","timestamp":1790694163228,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Telethon Perth Children\u2019s Hospital Research Fund"},{"name":"Raine Clinician Research Fellowship"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen & Gen Med"],"published-print":{"date-parts":[[2019,2]]},"abstract":"Abstract<\/jats:title>Background<\/jats:title>Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR<\/jats:styled-content>22A to LCR<\/jats:styled-content>22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region.<\/jats:p><\/jats:sec>Methods<\/jats:title>We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR<\/jats:styled-content>22B and LCR<\/jats:styled-content>22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR<\/jats:styled-content>22A and LCR<\/jats:styled-content>22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues.<\/jats:p><\/jats:sec>Results<\/jats:title>We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD<\/jats:styled-content>), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR<\/jats:styled-content>22B and LCR<\/jats:styled-content>22D to identify nine genes (ZNF<\/jats:styled-content>74, KLHL<\/jats:styled-content>22, MED<\/jats:styled-content>15, PI<\/jats:styled-content>4KA<\/jats:styled-content>, SERPIND<\/jats:styled-content>1, CRKL<\/jats:styled-content>, AIFM<\/jats:styled-content>3, SLC<\/jats:styled-content>7A4, and BCRP<\/jats:styled-content>2)<\/jats:italic> with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI<\/jats:styled-content>4KA<\/jats:styled-content><\/jats:italic> is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI<\/jats:styled-content>4KA<\/jats:styled-content><\/jats:italic> to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype\u2013phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.507","type":"journal-article","created":{"date-parts":[[2019,1,7]],"date-time":"2019-01-07T02:30:09Z","timestamp":1546828209000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Atypical nested 22q11.2 duplications between LCR<\/scp>22B and LCR<\/scp>22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance"],"prefix":"10.1002","volume":"7","author":[{"given":"Karen J.","family":"Woodward","sequence":"first","affiliation":[{"name":"Diagnostic Genomics PathWest Laboratory Medicine Perth Western Australia Australia"},{"name":"School of Biomedical Sciences University of Western Australia Perth Western Australia 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