{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T03:05:15Z","timestamp":1778036715196,"version":"3.51.4"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"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:p>GCK-MODY is a genetic condition characterized by alterations in the <jats:italic>GCK<\/jats:italic> gene, which can include several types of inactivating genetic variants - ranging from missense and nonsense variants, and splice site variants, to small and large deletions and insertions in the gene. This disorder primarily affects glucose homeostasis and usually presents in heterozygous individuals. Although GCK-MODY is a well-studied condition, some variant carriers may manifest symptoms that deviate from the typical disease phenotype. Our study identified two Brazilian patients with GCK-MODY carrying novel frameshift variants, one of whom presented atypical manifestations of the disease. The patient is a 14-year-old male harboring a variant c.398del; p.(Phe133SerfsTer7) in the <jats:italic>GCK<\/jats:italic> gene. He presented with the typical clinical features of GCK-MODY, including mild and stable fasting hyperglycemia, however, he also presented a history of polyuria and polydipsia, which are unusual symptoms of the disease. These symptoms could be associated with the more severe impact of a frameshift variant. However, we did not observe the same unusual phenotype in our second patient, who is a 15-year-old normal-weight female. At the age of 8, she was diagnosed with diabetes mellitus. The patient with the p.(Val335ArgfsTer124) variant presented with mild, stable hyperglycemia, a characteristic feature of the disease. In this study, we present two cases of novel frameshift variants in <jats:italic>GCK<\/jats:italic> and review other reports in the literature that have shown patients with atypical manifestations of the disease and highlight the importance of a comprehensive characterization of the phenotypic spectrum caused by GCK-MODY variants.<\/jats:p>","DOI":"10.3389\/fendo.2025.1549279","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T04:11:45Z","timestamp":1744690305000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: New insights about clinical manifestations of patients with GCK genetic variants"],"prefix":"10.3389","volume":"16","author":[{"given":"Ritiele Bastos","family":"de Souza","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella de Medeiros","family":"Abreu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00edlia Chaves","family":"Bernardo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta Magalh\u00e3es","family":"Tarantino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Rodacki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lenita","family":"Zajdenverg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda Ferreira","family":"de Andrade","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah Snaider","family":"Nicolay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Carolina Proen\u00e7a","family":"da Fonseca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaio Cezar Rodrigues","family":"Salum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata","family":"Szundy Berardo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge Luiz","family":"Luescher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ver\u00f4nica Marques","family":"Zembrzuski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro Hernan","family":"Cabello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Campos Junior","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41572-023-00421-w","article-title":"Monogenic diabetes","volume":"9","author":"Bonnefond","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S179793","article-title":"Maturity-onset diabetes of the young (MODY): Current perspectives on diagnosis and treatment","volume":"12","author":"Urakami","year":"2019","journal-title":"Diab Metab Syndr Obes"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/356162a0","article-title":"Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus","volume":"356","author":"Froguel","year":"1992","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2020.107640","article-title":"Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review","volume":"35","author":"Aarthy","year":"2021","journal-title":"J Diabetes Complic"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/dc21-S002","article-title":"2. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2021","volume":"44","author":"Care","year":"2021","journal-title":"Diabetes Care"},{"key":"B6","doi-asserted-by":"publisher","first-page":"15","DOI":"10.4239\/wjd.v15.i1.15","article-title":"Management of monogenic diabetes in pregnancy: A narrative review","volume":"15","author":"Jeeyavudeen","year":"2024","journal-title":"World J Diabetes"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13001","article-title":"Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia","volume":"10","author":"Wang","year":"2019","journal-title":"J Diabetes Investig"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/mgg3.728","article-title":"Association of a homozygous GCK missense mutation with mild diabetes","volume":"7","author":"Marucci","year":"2019","journal-title":"Mol Genet Genom Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/genes13010117","article-title":"Role of actionable genes in pursuing a true approach of precision medicine in monogenic diabetes","volume":"13","author":"Marucci","year":"2022","journal-title":"Genes (Basel)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21110","article-title":"Update on mutations in glucokinase ( GCK ), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia","volume":"30","author":"Osbak","year":"2009","journal-title":"Hum Mutat"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00148","article-title":"The central role of glucokinase in glucose homeostasis: A perspective 50 years after demonstrating the presence of the enzyme in islets of Langerhans","volume":"10","author":"Matschinsky","year":"2019","journal-title":"Front Physiol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"995","DOI":"10.33549\/physiolres.934487","article-title":"Clinical implications of the glucokinase impaired function \u2013 GCK MODY today","volume":"69","author":"Hul\u00edn","year":"2020","journal-title":"Physiol Res"},{"key":"B13","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1371\/journal.pone.0065326","article-title":"Use of hbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies","volume":"8","author":"Steele","year":"2013","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-2769","article-title":"Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation","volume":"38","author":"Chakera","year":"2015","journal-title":"Diabetes Care"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.283980","article-title":"Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia","volume":"311","author":"Steele","year":"2014","journal-title":"JAMA - J Am Med Assoc"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-3075-x","article-title":"Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia","volume":"57","author":"Stride","year":"2014","journal-title":"Diabetologia"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13098-021-00716-6","article-title":"Clinical and genetic features of maturity-onset diabetes of the young in pediatric patients: a 12-year monocentric experience","volume":"13","author":"Passanisi","year":"2021","journal-title":"Diabetol Metab Syndr"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.13426","article-title":"ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents","volume":"23","author":"Greeley","year":"2022","journal-title":"Pediatr Diabetes"},{"key":"B19","doi-asserted-by":"publisher","first-page":"4034","DOI":"10.3390\/ijms24044034","article-title":"\u201cPesto\u201d Mutation: phenotypic and genotypic characteristics of eight GCK\/MODY Ligurian patients","volume":"24","author":"Salina","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-02574","article-title":"Copy number variation in GCK in patients with maturity-onset diabetes of the young","volume":"104","author":"Berberich","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.108791","article-title":"Maturity onset diabetes of the young type 2 (MODY2): Insight from an extended family","volume":"175","author":"Elias-Assad","year":"2021","journal-title":"Diabetes Res Clin Pract"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/genes13112104","article-title":"A novel GCK large genomic rearrangement in a patient with MODY-2 detected by clinical exome sequencing","volume":"13","author":"Concolino","year":"2022","journal-title":"Genes (Basel)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s40842-019-0091-x","article-title":"Atypical hyperglycemia presentation suggests considering a diagnostic of other types of diabetes: first reported GCK-MODY in Per\u00fa","volume":"6","author":"Lizarzaburu-Robles","year":"2020","journal-title":"Clin Diabetes Endocrinol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2015-0354","article-title":"GCK mutations in Chinese MODY2 patients: A family pedigree report and review of Chinese literature","volume":"29","author":"Ping Xiao","year":"2016","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-0681","article-title":"Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY)","volume":"33","author":"Cuesta-M\u0169noz","year":"2010","journal-title":"Diabetes Care"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s13312-020-2032-2","article-title":"Genotype-phenotype characteristics of Turkish children with glucokinase mutations associated maturity-onset diabetes of the young","volume":"57","author":"Bolu","year":"2020","journal-title":"Indian Pediatr"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/S42000-021-00330-1","article-title":"Childhood-onset mild diabetes caused by a homozygous novel variant in the glucokinase gene","volume":"21","author":"Filibeli","year":"2022","journal-title":"Hormones (Athens)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu360","article-title":"Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability","volume":"23","author":"Raimondo","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B29","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1055\/s-2004-820967","article-title":"A novel nonsense mutation in GCK exon 9 co-segregates with diabetes phenotype","volume":"112","author":"Knebel","year":"2004","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2012.10.013","article-title":"MODY 2: Mutation identification and molecular ancestry in a Brazilian family","volume":"512","author":"Mota","year":"2013","journal-title":"Gene"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9010288","article-title":"Maturity-onset diabetes of the young (MODY) in Portugal: Novel GCK, HNFA1 and HNFA4 mutations","volume":"9","author":"Alvelos","year":"2020","journal-title":"J Clin Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2018.07.036","article-title":"Novel deletion mutation in the glucokinase gene from a Korean man with GCK-MODY phenotype and situs inversus","volume":"143","author":"Cho","year":"2018","journal-title":"Diabetes Res Clin Pract"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.4461","article-title":"Phenotype heterogeneity in glucokinase\u2013maturity-onset diabetes of the young (GCK-MODY) patients","volume":"9","author":"W\u0119drychowicz","year":"2017","journal-title":"JCRPE J Clin Res Pediatr Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13059-023-02935-8","article-title":"A comprehensive map of human glucokinase variant activity","volume":"24","author":"Gersing","year":"2023","journal-title":"Genome Biol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1549279\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T04:11:47Z","timestamp":1744690307000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1549279\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,15]]},"references-count":34,"alternative-id":["10.3389\/fendo.2025.1549279"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1549279","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,15]]},"article-number":"1549279"}}