{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:42:02Z","timestamp":1790808122664,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Juvenile-onset diabetes may occur in the context of a rare syndromic presentation, suggesting a monogenic etiology rather than a common multifactorial diabetes. In the present study, we report the case of a young diabetic Tunisian patient presenting learning problems, speech deficits, short stature, brachydactyly, and a normal weight. Whole exome sequencing analysis revealed five heterozygous genetic variants in <jats:italic>BBS1, BBS4, BBS8, MKS1<\/jats:italic>, and <jats:italic>CEP290<\/jats:italic>. These genes are involved in the regulation of cilium biogenesis and function. We analyzed variant combinations pathogenicity using the recently developed ORVAL tool, and we hypothesized that cumulative synergetic effects of these variants could explain the syndromic phenotype observed in our patient. Therefore, our investigation suggested a genetic diagnosis of Bardet\u2013Biedl syndrome with an oligogenic inheritance pattern rather than a monogenic diabetes. Although there is no curative therapy for this ciliopathy at the moment, a genetic diagnosis may offer other supportive care options, including the prevention of other possible clinical manifestations of this syndrome, mainly renal abnormalities, obesity, liver fibrosis, and hypertension, as well as the genetic counseling for family members.<\/jats:p>","DOI":"10.3389\/fgene.2021.664963","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T21:43:03Z","timestamp":1633556583000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Multiallelic Rare Variants in BBS Genes Support an Oligogenic Ciliopathy in a Non-obese Juvenile-Onset Syndromic Diabetic Patient: A Case Report"],"prefix":"10.3389","volume":"12","author":[{"given":"Hamza","family":"Dallali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Kheriji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafa","family":"Kammoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Mrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manel","family":"Soltani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajer","family":"Trabelsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid","family":"Hamdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afef","family":"Bahlous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melika","family":"Ben Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faten","family":"Mahjoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henda","family":"Jamoussi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Abdelhak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rym","family":"Kefi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"B1","unstructured":"Bardet-Biedl Syndrome Overview\u2014GeneReviews\u00ae\u2014NCBI Bookshelf2020"},{"key":"B2","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s00005-016-0432-8","article-title":"Genetic factors of diabetes","volume":"64","author":"Antosik","year":"2016","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"B3","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1080\/13816810802216464","article-title":"Bardet-biedl syndrome: an atypical phenotype in brothers with a proven BBS1 mutation","volume":"29","author":"Cannon","year":"2008","journal-title":"Ophthalmic Genet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"680838","DOI":"10.3389\/fgene.2021.680838","article-title":"Oligogenic Inheritance of Monoallelic TRIP11, FKBP10, NEK1, TBX5, and NBAS variants leading to a phenotype similar to odontochondrodysplasia","volume":"12","author":"Costantini","year":"2021","journal-title":"Front. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1083\/jcb.201006105","article-title":"CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content","volume":"190","author":"Craige","year":"2010","journal-title":"J. Cell Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1007\/s00592-018-01283-5","article-title":"Genetic characterization of suspected MODY patients in Tunisia by targeted next-generation sequencing","volume":"56","author":"Dallali","year":"2019","journal-title":"Acta Diabetol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/nar\/gkp215","article-title":"Human splicing finder: an online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"W545","DOI":"10.1093\/nar\/gky471","article-title":"VarAFT: a variant annotation and filtration system for human next generation sequencing data","volume":"46","author":"Desvignes","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1002\/humu.21480","article-title":"BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition","volume":"32","author":"Deveault","year":"2011","journal-title":"Hum. Mutat."},{"key":"B10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.atg.2015.10.001","article-title":"Comparison of two next-generation sequencing kits for diagnosis of epileptic disorders with a user-friendly tool for displaying gene coverage, DeCovA","volume":"7","author":"Dimassi","year":"2015","journal-title":"Appl. Transl. Genom."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1001\/archophthalmol.2012.2434","article-title":"BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl Syndrome","volume":"130","author":"Estrada-Cuzcano","year":"2012","journal-title":"Arch. Ophthalmol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1136\/jmg.40.8.e104","article-title":"Further support for digenic inheritance in Bardet-Biedl syndrome","volume":"40","author":"Fauser","year":"2003","journal-title":"J. Med. Genet."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1101\/2021.04.30.442110","article-title":"A comparison of tools for copy-number variation detection in germline whole exome and whole genome sequencing data","author":"Gabrielaite","year":"2021","journal-title":"bioRxiv"},{"key":"B14","doi-asserted-by":"publisher","first-page":"D900","DOI":"10.1093\/nar\/gkv1068","article-title":"DIDA: A curated and annotated digenic diseases database","volume":"44","author":"Gazzo","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e0173399","DOI":"10.1371\/journal.pone.0173399","article-title":"The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling","volume":"12","author":"Goetz","year":"2017","journal-title":"PLoS ONE"},{"key":"B16","doi-asserted-by":"publisher","first-page":"14416","DOI":"10.1038\/s41598-021-93878-2","article-title":"Benchmarking germline CNV calling tools from exome sequencing data","volume":"11","author":"Gordeeva","year":"2021","journal-title":"Sci. Rep."},{"key":"B17","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1111\/pedi.12772","article-title":"ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents","volume":"19","author":"Hattersley","year":"2018","journal-title":"Pediatr. Diabetes"},{"key":"B18","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1038\/s10038-020-0778-y","article-title":"Bardet\u2013Biedl syndrome and related disorders in Japan","volume":"65","author":"Hirano","year":"2020","journal-title":"J. Hum. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"R65","DOI":"10.1093\/hmg\/ddh092","article-title":"The oligogenic properties of Bardet-Biedl syndrome","volume":"13","author":"Katsanis","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/cge.12737","article-title":"Genetics of human Bardet-Biedl syndrome, an updates","volume":"90","author":"Khan","year":"2016","journal-title":"Clin. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"17335","DOI":"10.1038\/s41598-018-35614-x","article-title":"A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery","volume":"8","author":"Kilander","year":"2018","journal-title":"Sci. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"sa2","DOI":"10.7554\/eLife.53910.sa2","article-title":"Structure of the human BBSome core complex","volume":"9","author":"Klink","year":"2020","journal-title":"Elife"},{"key":"B23","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/ng.97","article-title":"Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome","volume":"40","author":"Leitch","year":"2008","journal-title":"Nat. Genet."},{"key":"B24","first-page":"471","article-title":"Primary cilium, an unsung hero in maintaining functional \u03b2-cell population","volume":"92","author":"Lodh","year":"2019","journal-title":"Yale J. Biol. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1093\/hmg\/ddv447","article-title":"Differential effects on \u03b2-cell mass by disruption of Bardet-Biedl syndrome or Alstrom syndrome genes","volume":"25","author":"Lodh","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"B26","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1159\/000357054","article-title":"Update on the Genetics of Bardet-Biedl Syndrome","volume":"5","author":"M'hamdi","year":"","journal-title":"Mol. Syndromol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1111\/cge.12129","article-title":"Clinical and genetic characterization of Bardet-Biedl syndrome in Tunisia: defining a strategy for molecular diagnosis","volume":"85","author":"M'hamdi","year":"","journal-title":"Clin. Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1159\/000276763","article-title":"A Novel Familial BBS12 mutation associated with a mild phenotype: implications for clinical and molecular diagnostic strategies","volume":"1","author":"Pawlik","year":"2010","journal-title":"Mol. Syndromol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1093\/bioinformatics\/bts526","article-title":"A robust model for read count data in exome sequencing experiments and implications for copy number variant calling","volume":"28","author":"Plagnol","year":"2012","journal-title":"Bioinformatics"},{"key":"B30","doi-asserted-by":"publisher","first-page":"W93","DOI":"10.1093\/nar\/gkz437","article-title":"ORVAL: a novel platform for the prediction and exploration of disease-causing oligogenic variant combinations","volume":"47","author":"Renaux","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s11892-018-1024-2","article-title":"Monogenic diabetes in children and adolescents: recognition and treatment options","volume":"18","author":"Sanyoura","year":"2018","journal-title":"Curr. Diab. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41439-019-0045-y","article-title":"A novel compound heterozygous mutation in TTC8 identified in a Japanese patient","volume":"6","author":"Sato","year":"2019","journal-title":"Hum. Genome Var."},{"key":"B33","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3389\/fgene.2019.00021","article-title":"Identification and characterization of known biallelic mutations in the IFT27 (BBS19) gene in a novel family with bardet-biedl syndrome","volume":"10","author":"Schaefer","year":"2019","journal-title":"Front. Genet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR : functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"10602","DOI":"10.1073\/pnas.1000219107","article-title":"Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome","volume":"107","author":"Zaghloul","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B36","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1093\/hmg\/ddt394","article-title":"BBS mutations modify phenotypic expression of CEP290-related ciliopathies","volume":"23","author":"Zhang","year":"2014","journal-title":"Hum. Mol. Genet."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.664963\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T21:43:07Z","timestamp":1633556587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.664963\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,6]]},"references-count":36,"alternative-id":["10.3389\/fgene.2021.664963"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.664963","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,6]]},"article-number":"664963"}}