{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T17:52:10Z","timestamp":1793987530297,"version":"4.8.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T00:00:00Z","timestamp":1741564800000},"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. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Skeletal dysplasia (SD) is a large and heterogeneous group of rare genetic disorders that affects bone and cartilage growth. These disorders are diagnosed based on radiographic, clinical, and molecular criteria. However, the diagnostics is challenging due to clinical and genetic heterogeneity. We present the experience of systematic use of comprehensive genetic testing in the national health system and the molecular epidemiology of SD in Slovenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We retrospectively reviewed 470 patients with clinical features of SD, including prenatal, childhood, and adult patients referred for diagnostic genetic evaluation to the national genetic reference center over ten years. In 262 patients, whole exome or whole genome sequencing was performed, while direct gene sequencing was performed in 208 patients with a specific clinical diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A definitive genetic diagnosis using NGS was achieved in 50% (n=131) of patients. Among the positive cases, 49.61% initially presented with a nonspecific diagnosis of SD, and genetic testing contributed to establishing the diagnosis. Moreover, we demonstrated high genetic heterogeneity in our SD cohort with 66 distinct causative genes, resulting in different types of SD. In detail, we detected 132 causative variants, of which 29 were novel, which expanded the mutational spectrum of SD. Furthermore, pathogenic copy number variants (CNVs) were identified in 4.55% of the total number of variants, highlighting the importance of CNV analysis in expanding the yield of molecular diagnosis of SD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>With the systematic use of WES and WGS, we have significantly improved the diagnostic yield of SD in the national health system and access to genetic testing. Moreover, we found significant genetic heterogeneity, and we report the genetic epidemiology of SD in the Slovenian population.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1523737","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T05:14:53Z","timestamp":1741583693000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Unraveling the complexity of skeletal dysplasias in the national health system"],"prefix":"10.3389","volume":"16","author":[{"given":"Dorra","family":"Najjar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ale\u0161","family":"Maver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Peterlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Jakli\u010d","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borut","family":"Peterlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.v155.5","article-title":"Nosology and classification of genetic skeletal disorders: 2010 revision","volume":"155","author":"Warman","year":"2011","journal-title":"Am J Med Genet Part A"},{"key":"B2","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1186\/s13023-019-1222-2","article-title":"The evolving therapeutic landscape of genetic skeletal disorders","volume":"14","author":"Sabir","year":"2019","journal-title":"Orphanet J Rare Diseases"},{"key":"B3","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1186\/s13023-023-02884-2","article-title":"The burden of hospital admissions for skeletal dysplasias in Sri Lanka: a population-based study","volume":"18","author":"Kolambage","year":"2023","journal-title":"Orphanet J Rare Diseases"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2015.03.003","article-title":"Skeletal dysplasias","volume":"42","author":"Krakow","year":"2015","journal-title":"Clinics perinatology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev-genom-090314-045904","article-title":"Advances in skeletal dysplasia genetics","volume":"16","author":"Geister","year":"2015","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.v191.5","article-title":"Nosology of genetic skeletal disorders: 2023 revision","volume":"191","author":"Unger","year":"2023","journal-title":"Am J Med Genet A"},{"key":"B7","doi-asserted-by":"publisher","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 Part A"},{"key":"B8","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/1750-1172-7-55","article-title":"A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012","volume":"7","author":"Cui","year":"2012","journal-title":"Orphanet J Rare Diseases"},{"key":"B9","doi-asserted-by":"publisher","first-page":"670842","DOI":"10.1155\/2014\/670842","article-title":"Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders","volume":"2014","author":"Faruqi","year":"2014","journal-title":"BioMed Res Int"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.129","article-title":"Comprehensive genetic exploration of skeletal dysplasia using targeted exome sequencing","volume":"18","author":"Bae","year":"2016","journal-title":"Genet Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2333794x21994998","DOI":"10.1177\/2333794X21994998","article-title":"The health & Economic disparities of congenital musculoskeletal disease worldwide: an analysis of 25 years (1992-2017)","volume":"8","author":"Mody","year":"2021","journal-title":"Glob Pediatr Health"},{"key":"B12","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s00198-020-05548-0","article-title":"Burden of disease associated with X-linked hypophosphataemia in adults: a systematic literature review","volume":"32","author":"Seefried","year":"2021","journal-title":"Osteoporosis Int"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-4642(20)30056-0","article-title":"The changing world of skeletal dysplasia","volume":"4","author":"Calder","year":"2020","journal-title":"Lancet Child Adolesc Health"},{"key":"B14","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.bone.2016.07.020","article-title":"Genomic approaches to diagnose rare bone disorders","volume":"102","author":"Falardeau","year":"2017","journal-title":"Bone"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1517\/21678707.2015.1083853","article-title":"New therapeutic targets in rare genetic skeletal diseases","volume":"3","author":"Briggs","year":"2015","journal-title":"Expert Opin orphan Drugs"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.142","article-title":"Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases","volume":"20","author":"Bergant","year":"2018","journal-title":"Genet Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.22","article-title":"Phenotype-driven gene target definition in clinical genome-wide sequencing data interpretation","volume":"18","author":"Ales","year":"2016","journal-title":"Genet Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3390\/life11030205","article-title":"Whole-genome sequencing in diagnostics of selected Slovenian undiagnosed patients with rare disorders","volume":"11","author":"Bergant","year":"2021","journal-title":"Life"},{"key":"B19","doi-asserted-by":"publisher","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":"B20","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2020-107303","article-title":"Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders","volume":"59","author":"Molina-Ram\u00edrez","year":"2022","journal-title":"J Med Genet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1206","article-title":"In silico prediction of splice-altering single nucleotide variants in the human genome","volume":"42","author":"Jian","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz431","article-title":"ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions","volume":"35","author":"Dolzhenko","year":"2019","journal-title":"Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.2013.43.issue-1","article-title":"From fastQ data to high-confidence variant calls: the genome analysis toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr Protoc Bioinf"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2013.183","article-title":"Assessing the necessity of confirmatory testing for exome-sequencing results in a clinical molecular diagnostic laboratory","volume":"16","author":"Strom","year":"2014","journal-title":"Genet Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1205","article-title":"OMIM.org: Online Mendelian Inheritance in Man (OMIM\u00ae), an online catalog of human genes and genetic disorders","volume":"43","author":"Amberger","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1080\/02763869.2020.1826228","article-title":"PubMed 2.0","volume":"39","author":"White","year":"2020","journal-title":"Medical Reference Services Quarterly"},{"key":"B29","doi-asserted-by":"publisher","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":"B30","unstructured":"ClinGen the clinical genome resource\n          \n          \n          2015"},{"key":"B31","volume-title":"ACGS best practice guidelines for variant classification in rare","author":"Durkie","year":"2023"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0170365","article-title":"Clinical practice guidelines for rare diseases: the orphanet database","volume":"12","author":"Pavan","year":"2017","journal-title":"PloS One"},{"key":"B34","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1136\/jmg-2022-108739","article-title":"Heterozygous pathogenic variants involving CBFB cause a new skeletal disorder resembling cleidocranial dysplasia","volume":"60","author":"Beyltjens","year":"2023","journal-title":"J Med Genet"},{"key":"B35","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1186\/s13023-021-02025-7","article-title":"Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia","volume":"16","author":"Scocchia","year":"2021","journal-title":"Orphanet J Rare Diseases"},{"key":"B36","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/gim.2015.148","article-title":"Clinical application of whole-exome sequencing across clinical indications","volume":"18","author":"Retterer","year":"2016","journal-title":"Genet Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01242-6","article-title":"Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Manickam","year":"2021","journal-title":"Genet Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s12687-020-00500-5","article-title":"Improving diagnostics of rare genetic diseases with NGS approaches","volume":"12","author":"Vink\u0161el","year":"2021","journal-title":"J Community Genet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.147","article-title":"Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort","volume":"18","author":"Shaheen","year":"2016","journal-title":"Genet Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2018.50","article-title":"Expanding the phenome and variome of skeletal dysplasia","volume":"20","author":"Maddirevula","year":"2018","journal-title":"Genet Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2018.10.026","article-title":"Phenotyping and genotyping of skeletal dysplasias: Evolution of a center and a decade of experience in India","volume":"120","author":"Uttarilli","year":"2019","journal-title":"Bone"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.v158a.5","article-title":"Clinical epidemiology of skeletal dysplasias in South America","volume":"158","author":"Barbosa-Buck","year":"2012","journal-title":"Am J Med Genet Part A"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.37766\/inplasy2023.5.0048","article-title":"Diagnostic yield of exome sequencing in fetuses with sonographic features of skeletal dysplasias but normal karyotype or chromosomal microarray analysis: A systematic review","volume":"14","author":"Tse","year":"2023","journal-title":"Genes"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23240","article-title":"Epidemiology of multiple congenital anomalies in europe: a EUROCAT population-based registry study","volume":"100","author":"Calzolari","year":"2014","journal-title":"Birth Defects Res Part A: Clin Mol Teratology."},{"key":"B45","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1186\/s13023-023-02955-4","article-title":"Genetic testing and diagnostic strategies of fetal skeletal dysplasia: a preliminary study in wuhan, china","volume":"18","author":"Liu","year":"2023","journal-title":"Orphanet J Rare Dis"},{"key":"B46","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3390\/ijns7010015","article-title":"Neonatal screening in europe revisited: an ISNS perspective on the current state and developments since 2010","volume":"7","author":"Loeber","year":"2021","journal-title":"Int J Neonatal Screen"},{"key":"B47","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1001\/jamapediatrics.2014.2465","article-title":"Universal state newborn screening programs can reduce health disparities","volume":"169","author":"Brosco","year":"2015","journal-title":"JAMA pediatrics"},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-67144-4_19","article-title":"Newborn screening: beyond the spot","volume-title":"Rare diseases epidemiology: update overview","author":"Urv","year":"2017"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302575110","article-title":"Clinical genomic database","volume":"110","author":"Solomon","year":"2013","journal-title":"Proc Natl Acad Sci"},{"key":"B50","unstructured":"Orpha data\n          \n          \n            \n              Orphanet\n              AS\n            \n          \n          \n          2011"},{"key":"B51","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1002\/ajmg.c.31874","article-title":"An online compendium of treatable genetic disorders","author":"Bick","year":"2021","journal-title":"Am J Med Genet Part C"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35246","article-title":"Clinical epidemiology of skeletal dysplasias in south america\u2020","author":"Barbosa-Buck","year":"2012","journal-title":"Am J Med Genet."},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-3462","article-title":"Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia","volume":"101","author":"Whyte","year":"2016","journal-title":"J Clin Endocrinology"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.anpedi.2016.03.015","article-title":"Displasias esquel\u00e9ticas: nuevos tratamientos m\u00e9dicos","volume":"85","author":"Argente","year":"2016","journal-title":"An. pediatr. (2003. Ed. impr.)"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1523737\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T05:14:57Z","timestamp":1741583697000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1523737\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,10]]},"references-count":54,"alternative-id":["10.3389\/fendo.2025.1523737"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1523737","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,10]]},"article-number":"1523737"}}