{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T05:31:26Z","timestamp":1778045486513,"version":"3.51.4"},"reference-count":26,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Qatar National Research Fund\u2019s National Priorities Research Program","award":["NPRP11S-0110-180250"],"award-info":[{"award-number":["NPRP11S-0110-180250"]}]},{"name":"Qatar National Research Fund\u2019s National Priorities Research Program","award":["PPM1-1229-15002"],"award-info":[{"award-number":["PPM1-1229-15002"]}]},{"name":"Qatar National Research Fund\u2019s National Priorities Research Program","award":["SDR200054"],"award-info":[{"award-number":["SDR200054"]}]},{"name":"Qatar National Research Fund\u2019s National Priorities Research Program","award":["SDR400034"],"award-info":[{"award-number":["SDR400034"]}]},{"name":"Path to Precision Medicine Program","award":["NPRP11S-0110-180250"],"award-info":[{"award-number":["NPRP11S-0110-180250"]}]},{"name":"Path to Precision Medicine Program","award":["PPM1-1229-15002"],"award-info":[{"award-number":["PPM1-1229-15002"]}]},{"name":"Path to Precision Medicine Program","award":["SDR200054"],"award-info":[{"award-number":["SDR200054"]}]},{"name":"Path to Precision Medicine Program","award":["SDR400034"],"award-info":[{"award-number":["SDR400034"]}]},{"name":"Sidra Medicine\u2019s Precision Medicine Program Internal Research Fund","award":["NPRP11S-0110-180250"],"award-info":[{"award-number":["NPRP11S-0110-180250"]}]},{"name":"Sidra Medicine\u2019s Precision Medicine Program Internal Research Fund","award":["PPM1-1229-15002"],"award-info":[{"award-number":["PPM1-1229-15002"]}]},{"name":"Sidra Medicine\u2019s Precision Medicine Program Internal Research Fund","award":["SDR200054"],"award-info":[{"award-number":["SDR200054"]}]},{"name":"Sidra Medicine\u2019s Precision Medicine Program Internal Research Fund","award":["SDR400034"],"award-info":[{"award-number":["SDR400034"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Clefts of the lip and\/or palate (CL\/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL\/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means.<\/jats:p>","DOI":"10.3390\/genes14040849","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T09:12:59Z","timestamp":1680253979000},"page":"849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3483-2660","authenticated-orcid":false,"given":"Alya A.","family":"Al-Kurbi","sequence":"first","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha 34110, Qatar"},{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6469-1854","authenticated-orcid":false,"given":"Elbay","family":"Aliyev","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sana","family":"AlSa\u2019afin","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha 34110, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-3509","authenticated-orcid":false,"given":"Waleed","family":"Aamer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3317-9775","authenticated-orcid":false,"given":"Sasirekha","family":"Palaniswamy","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aljazi","family":"Al-Maraghi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Houda","family":"Kilani","sequence":"additional","affiliation":[{"name":"Division of Plastic and Craniofacial Surgery, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ammira Al-Shabeeb","family":"Akil","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell A.","family":"Stotland","sequence":"additional","affiliation":[{"name":"Division of Plastic and Craniofacial Surgery, Sidra Medicine, Doha 26999, Qatar"},{"name":"Department of Surgery, Weill Cornell Medical College, Doha 24144, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3150-1276","authenticated-orcid":false,"given":"Khalid A.","family":"Fakhro","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Hamad Bin Khalifa University, Doha 34110, Qatar"},{"name":"Department of Human Genetics, Sidra Medicine, Doha 26999, Qatar"},{"name":"Department of Genetic Medicine, Weill Cornell Medical College, Doha 24144, Qatar"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/35076601","article-title":"Genetics of craniofacial development and malformation","volume":"2","author":"Wilkie","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"242","DOI":"10.4161\/org.7.4.17926","article-title":"Palatogenesis: Engineering, pathways and pathologies","volume":"7","author":"Levi","year":"2011","journal-title":"Organogenesis"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.13005\/bpj\/1208","article-title":"Role of IRF6 Gene in Orofacial Clefting: A Systematic Review","volume":"10","author":"Chandrasekharan","year":"2017","journal-title":"Biomed. Pharmacol. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/mgg3.66","article-title":"Novel IRF6 mutations in families with Van Der Woude syndrome and popliteal pterygium syndrome from sub-Saharan Africa","volume":"2","author":"Butali","year":"2014","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/gim.2012.141","article-title":"Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole-exome databases","volume":"15","author":"Leslie","year":"2013","journal-title":"Genet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1755-8166-6-31","article-title":"De Novo 2.3 Mb microdeletion of 1q32. 2 involving the Van der Woude Syndrome locus","volume":"6","author":"Tan","year":"2013","journal-title":"Mol. Cytogenet."},{"key":"ref_7","first-page":"888","article-title":"Popliteal pterygium syndrome: A clinical study of three families and report of linkage to the Van der Woude syndrome locus on 1q32","volume":"36","author":"Lees","year":"1999","journal-title":"J. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fbioe.2015.00092","article-title":"Detection of genomic structural variants from next-generation sequencing data","volume":"3","author":"Tattini","year":"2015","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13073-018-0606-6","article-title":"Complex structural variants in Mendelian disorders: Identification and breakpoint resolution using short- and long-read genome sequencing","volume":"10","author":"Stephens","year":"2018","journal-title":"Genome Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1038\/ng.944","article-title":"Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome","volume":"43","author":"Carvalho","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bergant, G., Maver, A., and Peterlin, B. (2021). Whole-genome sequencing in diagnostics of selected slovenian undiagnosed patients with rare disorders. Life, 11.","DOI":"10.3390\/life11030205"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nrg3933","article-title":"Genetic variation and the de novo assembly of human genomes","volume":"16","author":"Chaisson","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/nrg3555","article-title":"Rare-disease genetics in the era of next-generation sequencing: Discovery to translation","volume":"14","author":"Boycott","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nbt.1904","article-title":"Structural variation in two human genomes mapped at single-nucleotide resolution by whole genome de novo assembly","volume":"29","author":"Li","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_15","first-page":"3970","article-title":"Point of Care Exome Sequencing Reveals Allelic and Phenotypic Heterogeneity Underlying Mendelian disease in Qatar","volume":"28","author":"Fakhro","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Fakhro, K.A., Yousri, N.A., Rodriguez-Flores, J.L., Robay, A., Staudt, M.R., Agosto-Perez, F., Salit, J., Malek, J.A., Suhre, K., and Jayyousi, A. (2015). Copy number variations in the genome of the Qatari population. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1991-5"},{"key":"ref_17","first-page":"5","article-title":"Popliteal pterygium syndrome: A rare entity","volume":"3","author":"Qasim","year":"2012","journal-title":"APSP J. Case Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1002\/ajmg.a.37791","article-title":"Van der Woude and Popliteal Pterygium Syndromes: Broad intrafamilial variability in a three-generation family with mutation in IRF6","volume":"170","author":"Busche","year":"2016","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1093\/bioinformatics\/btu431","article-title":"Gustaf: Detecting and correctly classifying SVs in the NGS twilight zone","volume":"30","author":"Trappe","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Da\u2019as, S.I., Aamer, W., Hasan, W., Al-Maraghi, A., Al-Kurbi, A., Kilani, H., AlRayahi, J., Zamel, K., Stotland, M.A., and Fakhro, K.A. (2020). PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development. Cells, 9.","DOI":"10.3390\/cells9081782"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Consortium","year":"2015","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_24","unstructured":"Exome, E.V.S.N.G. (2011). Sequencing Project (ESP), Exome Variant Server. Available online: http:\/\/evs.gs.washington.edu\/EVS\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14061","DOI":"10.1038\/ncomms14061","article-title":"Transient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast","volume":"8","author":"Jeffares","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"W21","DOI":"10.1093\/nar\/gkab402","article-title":"AnnotSV and knotAnnotSV: A web server for human structural variations annotations, ranking and analysis","volume":"49","author":"Geoffroy","year":"2021","journal-title":"Nucl. Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/4\/849\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:07:32Z","timestamp":1760123252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/4\/849"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,31]]},"references-count":26,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["genes14040849"],"URL":"https:\/\/doi.org\/10.3390\/genes14040849","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,31]]}}}