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Patients present with abnormal craniofacial features and widespread periosteal osteosclerosis affecting the ribs, skull, and long bones. Nonlethal forms of RNS have recently been reported. Biallelic mutations in the FAM20C gene, which encodes a Golgi serine\/threonine protein kinase that phosphorylates secretory pathway proteins, are responsible for RNS. In this study, we examined a Turkish family consisting of three patients by exome sequencing and found that the homozygous c.1071A\u2009&amp;gt;\u2009G transition at the second-to-last position of the 5\u2032 end of exon 5 gave rise to a synonymous variant (p.P357P) in FAM20C. Subsequent mRNA (cDNA) sequencing of FAM20C showed that the c.1071A\u2009&amp;gt;\u2009G substitution disrupted the splice junction and directed the splicing to a new location in intron 5, resulting in an in-frame 12 amino acid insertion into the protein. FAM20C is a serine\/threonine protein kinase that localizes to the Golgi apparatus by forming a homo- or hetero-dimer and\/or is secreted from the cell to phosphorylate secretory proteins. Functional analysis showed that the identified insertion did not disrupt either homo- or hetero-dimerization of the FAM20C protein. However, this variant protein failed to localize properly to the Golgi apparatus and exhibited poor secretion from the cell. All these findings suggest that the identified variant causing the 12 amino acid insertion is responsible for the nonlethal form of RNS in the family and provides mechanistic insight into the molecular pathogenesis of RNS.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf129","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T18:04:41Z","timestamp":1755021881000},"page":"1693-1704","source":"Crossref","is-referenced-by-count":1,"title":["A synonymous single nucleotide variant on the FAM20C gene causes non-lethal Raine syndrome"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4500-5668","authenticated-orcid":false,"given":"Bayram","family":"Toraman","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Department of Medical Biology, Karadeniz Technical University , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u0130dris","family":"Er","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Medical Biology, Karadeniz Technical University , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Burak Kaan","family":"Kasap","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Karadeniz Technical University, Institute of Health Sciences , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00dcmit","family":"Uzun","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Karadeniz Technical University, Institute of Health Sciences , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuba","family":"Din\u00e7er","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Medical Biology, Karadeniz Technical University , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00f6khan","family":"Y\u0131ld\u0131z","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Medical Biology, Karadeniz Technical University , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00fclay","family":"Karag\u00fczel","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, Karadeniz Technical University , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saadettin","family":"Kayipmaz","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Karadeniz Technical University , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ersan","family":"Kalay","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Department of Medical Biology and Genetics, Karadeniz Technical University , Trabzon ,","place":["Turkey"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"2025100608162163900_ref1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1002\/jbmr.3034","article-title":"Raine syndrome (OMIM #259775), caused by FAM20C mutation, is congenital Sclerosing Osteomalacia with cerebral calcification (OMIM 259660)","volume":"32","author":"Whyte","year":"2017","journal-title":"J Bone Miner Res"},{"key":"2025100608162163900_ref2","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1136\/jmg.26.12.786","article-title":"Unknown syndrome: microcephaly, hypoplastic nose, exophthalmos, gum hyperplasia, cleft palate, low set ears, and osteosclerosis","volume":"26","author":"Raine","year":"1989","journal-title":"J Med Genet"},{"key":"2025100608162163900_ref3","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1086\/522240","article-title":"Mutations in FAM20C are associated with lethal Osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development","volume":"81","author":"Simpson","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2025100608162163900_ref4","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1002\/ajmg.a.32022","article-title":"Raine syndrome: a rare lethal osteosclerotic bone dysplasia. 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