AUTHOR=de Souza Ritiele Bastos , Abreu Gabriella de Medeiros , Bernardo Marília Chaves , Tarantino Roberta Magalhães , Rodacki Melanie , Zajdenverg Lenita , de Andrade Amanda Ferreira , Nicolay Deborah Snaider , da Fonseca Ana Carolina Proença , Salum Kaio Cezar Rodrigues , Szundy Berardo Renata , Luescher Jorge Luiz , Zembrzuski Verônica Marques , Cabello Pedro Hernan , Campos Junior Mario 

TITLE=Case Report: New insights about clinical manifestations of patients with GCK genetic variants

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1549279

DOI=10.3389/fendo.2025.1549279

ISSN=1664-2392

ABSTRACT=GCK-MODY is a genetic condition characterized by alterations in the GCK 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 GCK 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 GCK 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.