{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:24:25Z","timestamp":1778631865607,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Classic criteria for a maturity-onset diabetes of the young (MODY) diagnosis are often unable to identify all subjects, and traditional Sanger sequencing, using a candidate gene approach, leads to a high prevalence of missed genetic diagnosis, classified as MODY-X. Next generation sequencing (NGS) panels provide a highly sensitive method even for rare forms. Methods: We investigated 28 pediatric subjects suspected for MODY-X, utilizing a 15-gene NGS panel for monogenic diabetes (MD). Results: NGS detected variants of uncertain significance (VUS), likely pathogenic or pathogenic for rarer subtypes of MODY, in six patients. We found variants in the wolframin gene (WFS1), traditionally not considered in MD genetic screening panels, in three patients; KCNJ11 gene mutation, typically responsible for neonatal diabetes and rarely causing isolated diabetes in adolescents; INS gene mutation; a variant in the HNF1B gene in a young male with diabetes on sulfonylurea treatment. Conclusion: In our cohort, the availability of an NGS panel for MD was determined for the correct identification of MD subtypes in six patients with MODY-X. Our study underlines how a precise diagnosis utilizing NGS may have an impact on the management of different forms of MODY and, thus, lead to a tailored treatment and enable genetic counselling of other family members.<\/jats:p>","DOI":"10.3390\/jpm12101613","type":"journal-article","created":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T01:43:11Z","timestamp":1665279791000},"page":"1613","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2526-5588","authenticated-orcid":false,"given":"Giulio","family":"Maltoni","sequence":"first","affiliation":[{"name":"Pediatric Unit, IRCCS AOU, S. Orsola-Malpighi, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2230-7148","authenticated-orcid":false,"given":"Roberto","family":"Franceschi","sequence":"additional","affiliation":[{"name":"Pediatric Unit, S. Chiara Hospital of Trento, 38122 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Di Natale","sequence":"additional","affiliation":[{"name":"Pediatric Unit, IRCCS AOU, S. Orsola-Malpighi, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Randa","family":"Al-Qaisi","sequence":"additional","affiliation":[{"name":"Pediatric Unit, IRCCS AOU, S. Orsola-Malpighi, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Greco","sequence":"additional","affiliation":[{"name":"Advanced Molecular Diagnostic Laboratory, Department CIBIO-DMA, University of Trento, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2541-5419","authenticated-orcid":false,"given":"Roberto","family":"Bertorelli","sequence":"additional","affiliation":[{"name":"Next Generation Sequencing Core Facility, LaBSSAH, Department CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9791-5316","authenticated-orcid":false,"given":"Veronica","family":"De Sanctis","sequence":"additional","affiliation":[{"name":"Next Generation Sequencing Core Facility, LaBSSAH, Department CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Quattrone","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Department CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vilma","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Applied Biomedical Research Center, CRBA, S. Orsola-Malpighi, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vittoria","family":"Cauvin","sequence":"additional","affiliation":[{"name":"Pediatric Unit, S. Chiara Hospital of Trento, 38122 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Zucchini","sequence":"additional","affiliation":[{"name":"Pediatric Unit, IRCCS AOU, S. Orsola-Malpighi, 40138 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/pedi.12426","article-title":"SWEET Study Group. A description of clinician reported diagnosis of type 2 diabetes and other non-type 1 diabetes included in a large international multicentered pediatric diabetes registry (SWEET)","volume":"17","author":"Pacaud","year":"2016","journal-title":"Pediatr. Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1210\/jc.2016-2490","article-title":"Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetes (ISPED). Monogenic Diabetes Accounts for 6.3% of Cases Referred to 15 Italian Pediatric Diabetes Centers During 2007 to 2012","volume":"102","author":"Delvecchio","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","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":"27","author":"Hattersley","year":"2018","journal-title":"Pediatr. Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ymgme.2014.09.007","article-title":"Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach","volume":"113","author":"Carmody","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.diabres.2016.06.008","article-title":"A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians","volume":"119","author":"Ang","year":"2016","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1177\/0004563213483458","article-title":"Maturity onset diabetes of the young: Identification and diagnosis","volume":"50","author":"McDonald","year":"2013","journal-title":"Ann. Clin. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s11892-015-0681-7","article-title":"Undiagnosed MODY: Time for Action","volume":"15","author":"Kleinberger","year":"2015","journal-title":"Curr. Diabetes Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1016\/j.diabres.2008.06.011","article-title":"Low prevalence of MODY2 and MODY3 mutations in Brazilian individuals with clinical MODY phenotype","volume":"81","author":"Furuzawa","year":"2008","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.diabres.2016.10.017","article-title":"Brazilian Monogenic Diabetes Study Group (BRASMOD). Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data","volume":"123","author":"Giuffrida","year":"2017","journal-title":"Diabetes Res. Clin. Pr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1590\/S0004-27302008000800020","article-title":"HNF1alpha mutations are present in half of clinically defined MODY patients in South-Brazilian individuals","volume":"52","author":"Maraschin","year":"2008","journal-title":"Arq. Bras. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"786","DOI":"10.2337\/diacare.24.4.786","article-title":"Prevalence of maturity-onset diabetes of the young mutations in Brazilian families with autosomal-dominant early-onset type 2 diabetes","volume":"24","author":"Moises","year":"2001","journal-title":"Diabetes Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/cge.12988","article-title":"Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families","volume":"92","author":"Santana","year":"2017","journal-title":"Clin. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/nrendo.2016.50","article-title":"Common and rare forms of diabetes mellitus: Towards a continuum of diabetes subtypes","volume":"12","author":"Flannick","year":"2016","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"405","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":"ref_15","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/ng2067","article-title":"Common variants in WFS1 confer risk of type 2 diabetes","volume":"39","author":"Sandhu","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"446","DOI":"10.3109\/14992027.2014.887230","article-title":"WFS1 mutations in hearing-impaired children","volume":"53","author":"Luotonen","year":"2014","journal-title":"Int. J. Audiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14460","DOI":"10.1073\/pnas.0906474106","article-title":"Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction","volume":"106","author":"Borowiec","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6314368","DOI":"10.1155\/2016\/6314368","article-title":"Genetic Analysis and Follow-Up of 25 Neonatal Diabetes Mellitus Patients in China","volume":"2016","author":"Cao","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/1753-0407.12879","article-title":"Association of common type 1 and type 2 diabetes gene variants with latent autoimmune diabetes in adults: A meta-analysis","volume":"11","author":"Ramu","year":"2019","journal-title":"J. Diabetes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.2337\/diabetes.54.11.3126","article-title":"Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5","volume":"54","author":"Clauin","year":"2005","journal-title":"Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S2213-8587(13)70059-7","article-title":"French NDM study group. Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: A prospective cohort study [corrected]","volume":"1","author":"Busiah","year":"2013","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e962","DOI":"10.1002\/mgg3.962","article-title":"Targeted sequencing identifies novel variants in common and rare MODY genes","volume":"7","author":"Caetano","year":"2019","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.1210\/clinem\/dgac002","article-title":"WFS1 Gene-associated Diabetes Phenotypes and Identification of a Founder Mutation in Southern India","volume":"19","author":"Chapla","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1038\/s41374-020-0408-5","article-title":"Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival","volume":"100","author":"Abreu","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Warncke, K., Eckert, A., Kapellen, T., Kummer, S., Raile, K., Dunstheimer, D., Grulich-Henn, J., Woelfle, J., Wenzel, S., and Hofer, S.E. (2022). Clinical presentation and long-term outcome of patients with KCNJ11\/ABCC8 variants: Neonatal diabetes or MODY in the DPV registry from Germany and Austria. Pediatr. Diabetes, 13.","DOI":"10.1111\/pedi.13390"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/17446651.2022.2035216","article-title":"The application of precision medicine in monogenic diabetes","volume":"17","author":"Barbetti","year":"2022","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_27","unstructured":"(2022, September 01). Gene-Disease Validity Details. Available online: https:\/\/search.clinicalgenome.org\/kb\/gene-validity\/CGGV:assertion_072e29f7-db97-40d9-9280-819706203c24-2022-06-16T160000.000Z."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/S0959-440X(98)80037-7","article-title":"The role of assembly in insulin\u2019s biosynthesis","volume":"8","author":"Dodson","year":"1998","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.ejmg.2016.09.016","article-title":"Clinical and molecular characterization of a novel INS mutation identified in patients with MODY phenotype","volume":"59","author":"Piccini","year":"2016","journal-title":"Eur. J. Med. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1093\/jmcb\/mjx039","article-title":"Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10","volume":"9","author":"Yan","year":"2017","journal-title":"J. Mol. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1210\/jc.2008-2189","article-title":"Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young","volume":"94","author":"Raile","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1210\/jc.2018-01696","article-title":"Frequency and Characteristics of MODY 1 (HNF4A Mutation) and MODY 5 (HNF1B Mutation): Analysis From the DPV Database","volume":"104","author":"Warncke","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Franceschi, R. (2022). Precision Medicine in Diabetes, Current Research and Future Perspectives. J. Pers. Med., 12.","DOI":"10.3390\/jpm12081233"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/10\/1613\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:44:31Z","timestamp":1760143471000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/10\/1613"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,30]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jpm12101613"],"URL":"https:\/\/doi.org\/10.3390\/jpm12101613","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,30]]}}}