20.500.12556/RUL-144418 A comprehensive genetic analysis of Slovenian families with multiple cases of orofacial clefts reveals novel variants in the genes IRF6, GRHL3, and TBX22 Although the aetiology of non-syndromic orofacial clefts (nsOFCs) is usually multifactorial, syndromic OFCs (syOFCs) are often caused by single mutations in known genes. Some syndromes, e.g., Van der Woude syndrome (VWS1; VWS2) and X-linked cleft palate with or without ankyloglossia (CPX), show only minor clinical signs in addition to OFC and are sometimes difficult to differentiate from nsOFCs. We recruited 34 Slovenian multi-case families with apparent nsOFCs (isolated OFCs or OFCs with minor additional facial signs). First, we examined IRF6, GRHL3, and TBX22 by Sanger or whole exome sequencing to identify VWS and CPX families. Next, we examined 72 additional nsOFC genes in the remaining families. Variant validation and co-segregation analysis were performed for each identified variant using Sanger sequencing, real-time quantitative PCR and microarray-based comparative genomic hybridization. We identified six disease-causing variants (three novel) in IRF6, GRHL3, and TBX22 in 21% of families with apparent nsOFCs, suggesting that our sequencing approach is useful for distinguishing syOFCs from nsOFCs. The novel variants, a frameshift variant in exon 7 of IRF6, a splice-altering variant in GRHL3, and a deletion of the coding exons of TBX22, indicate VWS1, VWS2, and CPX, respectively. We also identified five rare variants in nsOFC genes in families without VWS or CPX, but they could not be conclusively linked to nsOFC. genetics family study non-syndromic orofacial cleft Van der Woude syndrome X-linked cleft palate with or without ankyloglossia IRF6 GRHL3 TBX22 whole exome sequencing etiologija nesindromskih orofacialnih razcepov družinska študija nesindromski orofacialni razcep Van der Woudov sindrom X-povezana razcepka neba z ali brez ankiloglosije sekvenciranje celotnega eksoma genetika true false true Angleški jezik Slovenski jezik Članek v reviji 2023-02-21 12:17:02 2023-02-21 12:17:08 2023-02-22 03:32:21 0000-00-00 00:00:00 2023 0 0 19 str. iss. 5, art. 4262 Vol. 24 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 575 1422-0067 10.3390/ijms24054262 142479875 ijms-24-04262.pdf ijms-24-04262.pdf 1 3E3BC27679D41E9E8EBF9FC8EC2272E1 98267c8b64c709553b14dc48350beadb092a91f319ecb294fa6cf00b2b5eaa6a 2bc9279d-b1d9-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166726 https://www.mdpi.com/1422-0067/24/5/4262 1 ef4ba0ad-b1d8-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166725 Fakulteta za farmacijo 0 0 0