{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:32:27Z","timestamp":1787697147603,"version":"build-2784847793"},"reference-count":31,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T00:00:00Z","timestamp":1697155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003286","name":"Kuwait Foundation for the Advancement of Sciences (KFAS)","doi-asserted-by":"publisher","award":["P114-13MG-01"],"award-info":[{"award-number":["P114-13MG-01"]}],"id":[{"id":"10.13039\/501100003286","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003286","name":"Kuwait Foundation for the Advancement of Sciences (KFAS)","doi-asserted-by":"publisher","award":["(OMICSRU-RCF) SRUL02\/13"],"award-info":[{"award-number":["(OMICSRU-RCF) SRUL02\/13"]}],"id":[{"id":"10.13039\/501100003286","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health Sciences Center, Kuwait University","award":["P114-13MG-01"],"award-info":[{"award-number":["P114-13MG-01"]}]},{"name":"Health Sciences Center, Kuwait University","award":["(OMICSRU-RCF) SRUL02\/13"],"award-info":[{"award-number":["(OMICSRU-RCF) SRUL02\/13"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction: Primary ciliary dyskinesia (PCD) is a congenital thoracic disorder caused by dysfunction of motile cilia, resulting in insufficient mucociliary clearance of the lungs. The overall aim of this study is to identify causative defective genes in PCD-affected individuals in the Kuwaiti population. Methods: A cohort of multiple consanguineous PCD families was identified from Kuwaiti patients and genomic DNA from the family members was isolated using standard procedures. The DNA samples from all affected individuals were analyzed by whole exome sequencing (WES). Transmission electron microscopy (TEM) and immunofluorescent analysis (IF) were performed on samples obtained by nasal brushings to identify specific structural abnormalities within ciliated cells. Results: Here, we present six multiplex families with 11 patients who all presented with typical PCD symptoms. Ten out of eleven patients inherited a 3 bp homozygous deletion of GAA in RSPH9, whereas the eleventh patients inherited this variant in trans with a frameshift deletion in RSPH9. Genetic results were confirmed by segregation analysis. The in-frame deletion of GAA in RSPH9 has previously been published as pathogenic in both annotated RSPH9 transcript variants (1 and 2). In contrast, the previously unpublished RSPH9 frameshift deletion identified in KU-15.IV2 impacts only RSPH9 transcript variant two. Regarding all 11 PCD individuals analyzed, IF results demonstrated absence of RSPH9 protein and TEM analysis showed the typical findings in RSPH9 mutant individuals. Conclusions: We present the largest cohort of PCD individuals affected by the founder in-frame deletion GAA in RSPH9. This founder variant is the most common PCD-causing variant in Bedouin Arabs in Kuwait.<\/jats:p>","DOI":"10.3390\/jcm12206505","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T10:04:39Z","timestamp":1697191479000},"page":"6505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mapping the Most Common Founder Variant in RSPH9 That Causes Primary Ciliary Dyskinesia in Multiple Consanguineous Families of Bedouin Arabs"],"prefix":"10.3390","volume":"12","author":[{"given":"Dalal A.","family":"Al-Mutairi","sequence":"first","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait City 13110, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basel H.","family":"Alsabah","sequence":"additional","affiliation":[{"name":"Zain Hospital for Ear, Nose and Throat, Airport Road, Shuwaikh, Kuwait City 70030, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Pennekamp","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0282-6765","authenticated-orcid":false,"given":"Heymut","family":"Omran","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Muenster, 48149 Muenster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1002\/ppul.22577","article-title":"Longitudinal lung function and structural changes in children with primary ciliary dyskinesia","volume":"47","author":"Magnin","year":"2012","journal-title":"Pediatr. Pulmonol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1513\/pats.201103-023SD","article-title":"The emerging genetics of primary ciliary dyskinesia","volume":"8","author":"Zariwala","year":"2011","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S2213-2600(21)00453-7","article-title":"The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: A genetic database analysis","volume":"10","author":"Hannah","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1146\/annurev.physiol.69.040705.141301","article-title":"Genetic defects in ciliary structure and function","volume":"69","author":"Zariwala","year":"2007","journal-title":"Annu. Rev. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1164\/rccm.201301-0059CI","article-title":"Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease","volume":"188","author":"Knowles","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_6","first-page":"18","article-title":"Genetics and biology of primary ciliary dyskinesia","volume":"18","author":"Horani","year":"2016","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_7","first-page":"51","article-title":"Primary Ciliary Dyskinesia (PCD): A genetic disorder of motile cilia","volume":"4","author":"Leigh","year":"2019","journal-title":"Transl. Sci. Rare Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"R27","DOI":"10.1093\/hmg\/ddg061","article-title":"To beat or not to beat: Roles of cilia in development and disease","volume":"12","author":"Heintz","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.ajhg.2013.07.013","article-title":"Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects","volume":"93","author":"Kott","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ajhg.2009.01.011","article-title":"Mutations in Radial Spoke Head Protein Genes RSPH9 and RSPH4A Cause Primary Ciliary Dyskinesia with Central-Microtubular-Pair Abnormalities","volume":"84","author":"Castleman","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ajhg.2015.05.004","article-title":"RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes","volume":"97","author":"Jeanson","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.ajhg.2016.06.022","article-title":"Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility","volume":"99","author":"Thomas","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/cge.13742","article-title":"A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects","volume":"98","author":"Cho","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Anderegg, L., Im Hof Gut, M., Hetzel, U., Howerth, E.W., Leuthard, F., Kyostila, K., Lohi, H., Pettitt, L., Mellersh, C., and Minor, K.M. (2019). NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008378"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1017280","DOI":"10.3389\/fgene.2022.1017280","article-title":"Identification of a novel founder variant in DNAI2 cause primary ciliary dyskinesia in five consanguineous families derived from a single tribe descendant of Arabian Peninsula","volume":"13","author":"Alsabah","year":"2022","journal-title":"Front. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1002\/humu.22818","article-title":"Rapid Detection of Rare Deleterious Variants by Next Generation Sequencing with Optional Microarray SNP Genotype Data","volume":"36","author":"Watson","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1136\/jmg.2010.082081","article-title":"GeneScreen: A program for high-throughput mutation detection in DNA sequence electropherograms","volume":"48","author":"Carr","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/ng.2961","article-title":"Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia","volume":"46","author":"Wallmeier","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1164\/rccm.201311-2047OC","article-title":"Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype","volume":"189","author":"Knowles","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/humu.22220","article-title":"Autozygosity Mapping with Exome Sequence Data","volume":"34","author":"Carr","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1002\/humu.22322","article-title":"Simple and efficient identification of rare recessive pathologically important sequence variants from next generation exome sequence data","volume":"34","author":"Carr","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Niziolek, M., Bicka, M., Osinka, A., Samsel, Z., Sekretarska, J., Poprzeczko, M., Bazan, R., Fabczak, H., Joachimiak, E., and Wloga, D. (2022). PCD Genes-From Patients to Model Organisms and Back to Humans. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031749"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1469-1809.2009.00559.x","article-title":"Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families","volume":"74","author":"Reish","year":"2010","journal-title":"Ann. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/j.1469-1809.2012.00704.x","article-title":"From a single whole exome read to notions of clinical screening: Primary ciliary dyskinesia and RSPH9 p.Lys268del in the Arabian Peninsula","volume":"76","author":"Alsaadi","year":"2012","journal-title":"Ann. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1126\/science.2884728","article-title":"Homozygosity mapping: A way to map human recessive traits with the DNA of inbred children","volume":"236","author":"Lander","year":"1987","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/ng.2277","article-title":"CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms","volume":"44","author":"Panizzi","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.ajhg.2013.06.007","article-title":"ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6","volume":"93","author":"Zariwala","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/cge.13661","article-title":"Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia","volume":"97","author":"Fassad","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/j.ajhg.2019.04.011","article-title":"Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population","volume":"104","author":"Monies","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1165\/rcmb.2014-0483OC","article-title":"Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects","volume":"53","author":"Frommer","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6505\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:06:25Z","timestamp":1760130385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/20\/6505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,13]]},"references-count":31,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["jcm12206505"],"URL":"https:\/\/doi.org\/10.3390\/jcm12206505","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,13]]}}}