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
Laboratory of Human Genetics, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
Josué de Castro Nutrition Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Front Endocrinol (Lausanne). 2025 Apr 15;16:1549279. doi: 10.3389/fendo.2025.1549279. eCollection 2025.
GCK-MODY is a genetic condition characterized by alterations in the 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 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 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.
葡萄糖激酶基因（GCK）突变所致的成年发病型糖尿病（GCK-MODY）是一种由该基因突变引起的遗传性疾病，这些突变包括多种类型的失活基因变异，从错义突变、无义突变、剪接位点变异，到基因的小片段和大片段缺失及插入。这种疾病主要影响葡萄糖稳态，通常在杂合子个体中出现。尽管GCK-MODY是一种研究充分的疾病，但一些变异携带者可能表现出与典型疾病表型不同的症状。我们的研究发现了两名携带新型移码变异的巴西GCK-MODY患者，其中一名患者表现出该疾病的非典型症状。该患者是一名14岁男性，其基因存在c.398del变异；p.(Phe133SerfsTer7)。他表现出GCK-MODY的典型临床特征，包括轻度且稳定的空腹高血糖，然而，他还出现了多尿和多饮的病史，这在该疾病中并不常见。这些症状可能与移码变异的更严重影响有关。然而，我们在第二名患者中未观察到相同的异常表型，第二名患者是一名15岁体重正常的女性。她在8岁时被诊断出患有糖尿病。携带p.(Val335ArgfsTer124)变异的患者表现出轻度、稳定的高血糖，这是该疾病的特征性表现。在本研究中，我们报告了两例基因新型移码变异的病例，并回顾了文献中其他显示该疾病非典型表现患者的报告，强调了全面描述GCK-MODY变异所致表型谱的重要性。
