{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T13:00:07Z","timestamp":1775307607018,"version":"3.50.1"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["277843"],"award-info":[{"award-number":["277843"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9lius Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["21322"],"award-info":[{"award-number":["21322"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006129","name":"Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse","doi-asserted-by":"publisher","award":["2018-02645"],"award-info":[{"award-number":["2018-02645"]}],"id":[{"id":"10.13039\/501100006129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2020-00587"],"award-info":[{"award-number":["2020-00587"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004348","name":"Stockholm County Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004348","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Skeletal dysplasias are often well characterized, and only a minority of the cases remain unsolved after a thorough analysis of pathogenic variants in over 400 genes that are presently known to cause monogenic skeletal diseases. Here, we describe an 11-year-old Finnish girl, born to unrelated healthy parents, who had severe short stature and a phenotype similar to odontochondrodysplasia (ODCD), a monogenic skeletal dysplasia caused by biallelic <jats:italic>TRIP11<\/jats:italic> variants. The family had previously lost a fetus due to severe skeletal dysplasia. Exome sequencing and bioinformatic analysis revealed an oligogenic inheritance of a heterozygous nonsense mutation in <jats:italic>TRIP11<\/jats:italic> and four likely pathogenic missense variants in <jats:italic>FKBP10<\/jats:italic>, <jats:italic>TBX5<\/jats:italic>, <jats:italic>NEK1<\/jats:italic>, and <jats:italic>NBAS<\/jats:italic> in the index patient. Interestingly, all these genes except <jats:italic>TBX5<\/jats:italic> are known to cause skeletal dysplasia in an autosomal recessive manner. In contrast, the fetus was found homozygous for the <jats:italic>TRIP11<\/jats:italic> mutation, and achondrogenesis type IA diagnosis was, thus, molecularly confirmed, indicating two different skeletal dysplasia forms in the family. To the best of our knowledge, this is the first report of an oligogenic inheritance model of a skeletal dysplasia in a Finnish family. Our findings may have implications for genetic counseling and for understanding the yet unsolved cases of rare skeletal dysplasias.<\/jats:p>","DOI":"10.3389\/fgene.2021.680838","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T09:49:36Z","timestamp":1622627376000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Oligogenic Inheritance of Monoallelic TRIP11, FKBP10, NEK1, TBX5, and NBAS Variants Leading to a Phenotype Similar to Odontochondrodysplasia"],"prefix":"10.3389","volume":"12","author":[{"given":"Alice","family":"Costantini","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Valta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Maarit","family":"Suomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Outi","family":"M\u00e4kitie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fulya","family":"Taylan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.ajhg.2010.02.022","article-title":"Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta","volume":"86","author":"Alanay","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1038\/ejhg.2017.130","article-title":"SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population","volume":"25","author":"Ameur","year":"2017","journal-title":"Eur. J. Hum. Genet."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2639","DOI":"10.1091\/mbc.e08-11-1104","article-title":"Identification of the neuroblastoma-amplified gene product as a component of the syntaxin 18 complex implicated in Golgi-to-endoplasmic reticulum retrograde transport","volume":"20","author":"Aoki","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1002\/humu.22139","article-title":"Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix","volume":"33","author":"Barnes","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"655","DOI":"10.4161\/cc.10.4.14814","article-title":"Nek1 kinase functions in DNA damage response and checkpoint control through a pathway independent of ATM and ATR","volume":"10","author":"Chen","year":"2011","journal-title":"Cell Cycle"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1002\/jbmr.4177","article-title":"Novel RPL13 variants and variable clinical expressivity in a human ribosomopathy with spondyloepimetaphyseal dysplasia","volume":"36","author":"Costantini","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1016\/j.ajhg.2009.04.016","article-title":"DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III","volume":"84","author":"Dagoneau","year":"2009","journal-title":"Am. J. Hum. Genet"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e1000315","DOI":"10.1371\/journal.pgen.1000315","article-title":"The golgin GMAP210\/TRIP11 anchors IFT20 to the Golgi complex","volume":"4","author":"Follit","year":"2008","journal-title":"PLoS Genet."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1126\/science.aat5056","article-title":"Oligogenic inheritance of a human heart disease involving a genetic modifier","volume":"364","author":"Gifford","year":"2019","journal-title":"Science"},{"key":"ref10","first-page":"434","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume-title":"Nature","author":"Karczewski","year":"2020"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/brain\/awy290","article-title":"Integrated clinical and omics approach to rare diseases: novel genes and oligogenic inheritance in holoprosencephaly","volume":"142","author":"Kim","year":"2019","journal-title":"Brain"},{"key":"ref12","doi-asserted-by":"publisher","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":"ref13","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/ng0197-21","article-title":"Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family","volume":"15","author":"Li","year":"1997","journal-title":"Nat. Genet."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1136\/jmg.2009.074815","article-title":"Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huet anomaly","volume":"47","author":"Maksimova","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1038\/s41588-019-0528-2","article-title":"PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels","volume":"51","author":"Martin","year":"2019","journal-title":"Nat. Genet."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1136\/jmg.2010.081356","article-title":"Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib","volume":"48","author":"Maupetit-Mehouas","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.1002\/ajmg.a.61366","article-title":"Nosology and classification of genetic skeletal disorders: 2019 revision","volume":"179","author":"Mortier","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s00439-002-0875-3","article-title":"Finnish disease heritage I: characteristics, causes, background","volume":"112","author":"Norio","year":"2003","journal-title":"Hum. Genet."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e1003153","DOI":"10.1371\/journal.pcbi.1003153","article-title":"GEMINI: integrative exploration of genetic variation and genome annotations","volume":"9","author":"Paila","year":"2013","journal-title":"PLoS Comput. Biol."},{"key":"ref21","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":"ref22","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1091\/mbc.E14-10-1450","article-title":"Coupling of vesicle tethering and Rab binding is required for in vivo functionality of the golgin GMAP-210","volume":"26","author":"Sato","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.ajhg.2010.05.020","article-title":"FKBP10 and Bruck syndrome: phenotypic heterogeneity or call for reclassification?","volume":"87","author":"Shaheen","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1016\/j.febslet.2008.03.036","article-title":"The mammalian Nek1 kinase is involved in primary cilium formation","volume":"582","author":"Shalom","year":"2008","journal-title":"FEBS Lett."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1056\/NEJMoa0900158","article-title":"Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210","volume":"362","author":"Smits","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"W478","DOI":"10.1093\/nar\/gks402","article-title":"GeneCodis3: a non-redundant and modular enrichment analysis tool for functional genomics","volume":"40","author":"Tabas-Madrid","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1002\/jbmr.2834","article-title":"Spondyloocular syndrome: novel mutations in XYLT2 gene and expansion of the phenotypic spectrum","volume":"31","author":"Taylan","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.ajhg.2010.12.004","article-title":"NEK1 mutations cause short-rib polydactyly syndrome type majewski","volume":"88","author":"Thiel","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.ajhg.2017.04.010","article-title":"MARRVEL: integration of human and model organism genetic resources to facilitate functional annotation of the human genome","volume":"100","author":"Wang","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e124701","DOI":"10.1172\/jci.insight.124701","article-title":"Hypomorphic mutations of TRIP11 cause odontochondrodysplasia","volume":"4","author":"Wehrle","year":"2019","journal-title":"JCI Insight"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1001\/jama.2013.281053","article-title":"World medical association declaration of Helsinki: ethical principles for medical research involving human subjects","volume":"310","year":"2013","journal-title":"JAMA"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.680838\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T09:49:41Z","timestamp":1622627381000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.680838\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,2]]},"references-count":31,"alternative-id":["10.3389\/fgene.2021.680838"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.680838","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,2]]},"article-number":"680838"}}