Diabetes Mellitus With Positive Diabetes-Related Antibodies And Digenic Heterozygous Mutations:One Case Report And Literature Review

BackgroundDiabetes mellitus is a clinical syndrome with multiple etiologies,pathologies,and high heterogeneity,caused by a complex combination of genetic,environmental,behavioral and other factors[1].At present,patients with type 1 diabetes mellitus(T1 DM)and type 2 diabetes mellitus(T2DM)are still predominant in China.With the development of molecular genetic technology,more and more patients with monogenic diabetes have been found,especially maturity onset diabetes of the young(MODY).MODY is a group of monogenic diabetes mellitus with the common characteristic of islet β-cell dysfunction,characterized by a young age of onset,a family history of diabetes,no significant ketosis tendency,and no TlDM-related autoantibodies.However,due to the lack of unified diagnostic criteria,the symptoms are hidden,and the clinical phenotype overlaps with T1DM and T2DM,it is easy to be misdiagnosed as T1DM and T2DM.In addition,the clinical phenotypes of MODY patients are diverse and heterogeneous and there is no obvious genotype-phenotype correlation.Therefore,it is necessary to summarize and expand the genotypes and clinical phenotypes of MODY patients.The existence of positive diabetes-related antibodies is usually used as an exclusion criterion for MODY,and diabetic ketosis(DK)/diabetic ketoacidosis(DKA)is also rare in MODY patients.Only a few studies have been conducted in patients with maturity onset diabetes of the young type 1(MODY1),maturity onset diabetes of the young type 2(MODY2)and maturity onset diabetes of the young type 3(MODY3),and no studies have been found on positive diabetes-related antibodies and DK/DKA in patients with maturity onset diabetes of the young type 5(MODY5)and maturity onset diabetes of the young type 8(MODY8).Purpose1.In this study,we collected the clinical data of a patient and his family in our hospital,combined with case analysis and literature review to explore the potential relationship between HNF1B,CEL mutations and positive diabetes-related antibodies,DK/DKA,and the possible mechanism of positive diabetes-related antibodies and DK/DKA in MODY patients.2.Through literature review,the genotypes and clinical phenotypes of Chinese patients with MODY5 and MODY8 patients reported previously were summarized,so as to strengthen clinicians’ understanding of this rare disease.Methods1.In this study,we collected the clinical data from a patient with DK and positive diabetes-related antibodies in our hospital,and extracted peripheral blood for whole exome sequencing(WES).The mutation site was verified by the patient’s family members.The pathogenicity of the mutated gene was evaluated according to the 2015 American College of Medical Genetics(ACMG)sequence variation interpretation guidelines.2.Bioinformatics analysis software was used to predict the harmful degree of mutant genes.Clustal X 2.1 was used to analyze the conservation of mutation sites in homologous species,and AlphaFold 2.1 was used to construct the protein structure models of HNF1B and CEL wild-type and mutant proteins.3.In this study,case reports of MODY5 and MODY8 patients with positive diabetes-related antibodies or DK/DKA were searched in Chinese and English databases using relevant search terms,and their genotypes and clinical phenotypes were summarized.Chinese MODY5 patients and MODY8 patients were searched in the same way.According to whether they exhibited positive diabetes-related antibodies and DK/DKA,the patients were divided into antibody-positive and antibody-negative groups,and DK/DKA and non-DK/DKA groups.The general clinical data,laboratory examination results and genetic test results of the patients were collected,and SPSS 27.0 was used to analyze the statistical differences of the above data among the groups.The genotypes and phenotypes of Chinese MODY5 patients and MODY8 patients were analyzed and summarized.4.Through literature review,the possible mechanisms of positive diabetes-related antibodies and DK/DKA in MODY patients were analyzed.Results1.A 9-year-old boy was found to carry the heterozygous mutations of HNF1B p.D221V and CEL p.V123I by WES.His mother carried the same digenic heterozygous mutations,and his sister was a carrier of the same HNF1B heterozygous mutation.Both HNF1B and CEL mutations were defined as "variants of uncertain significance" according to the ACMG guidelines.2.Bioinformatics analysis software predicted that the HNF1B p.D221V and CEL p.V123I may be harmful.Multiple sequence alignment of mutation sites in homologous species revealed that the two mutation sites were highly conserved.After modeling the wild-type and mutant proteins of HNF1B and CEL,it was found that the polarity and protein-protein interaction of the HNF1B mutant protein were altered compared with the wild-type,while the CEL mutant protein was unaltered.3.Literature review found that all the MODY5 patients with positive diabetes-related antibodies were from China,and 80%of the MODY5 patients with DK/DKA were from China.There were no significant differences in general clinical data and laboratory examinations between the antibody-positive group and the antibody-negative group of Chinese MODY5 patients;Compared with the non-DK/DKA group,the DK/DKA group had significantly higher glycated hemoglobin(HbA1c)levels and lower number of patients with a family history of diabetes,the difference was statistically significant(P<0.05).Chinese MODY5 patients in DK/DKA group and non-DK/DKA group,positive diabetes-related antibodies group and negative group could have variants in the same exon region.There were no statistical differences in the type of gene mutation between the two groups.No MODY8 patients with positive diabetes-related antibodies and DK/DKA were found.4.The mechanisms underlying the emergence of positive diabetes-related antibodies in MODY patients are currently unknown,it may be associated with worsening glycemic control and may vary geographically.MODY patients may develop DK/DKA due to infection,stress and other triggers on the basis of poor blood glucose control.The mechanism needs to be further clarified,and the effect of genes cannot be excluded.5.HNF1B deletion is the main mutation in Chinese patients with MODY5,and the whole gene deletion of exons 1-9 is the most common,followed by mutations in the DNA-binding domain of the HNF1B gene.The majority of Chinese MODY5 patients diagnosed with diabetes before the age of 25 years with normal body size,can without a family history of diabetes.Most of them still have islet β-cell secretory functions.The main manifestations are renal cysts,hypomagnesemia,hyperuricemia,liver and kidney dysfunction,pancreatic hypoplasia,and urogenital malformations.Some patients with HNF1B deletion also have neurologic or psychiatric symptoms.6.MODY8 patients mainly had single base deletions in the proximal variable number of tandem repeats segments.Most patients with onset of diabetes were between 30 and 40 years of age.The main manifestations were low fecal elastase levels and structural changes in the pancreas.In addition,hyperlipidemia and vitamin D deficiency can also occur in some patients.Conclusions1.We reported a patient with DK and positive diabetes-related antibodies,who had digenic heterozygous mutations in both HNF1B and CEL.The patient was diagnosed with undetermined diabetes according to the latest diabetes classification guidelines,but combined with the clinical characteristics and genotype analysis,the diagnosis of MODY could not be excluded.In the future,protein function tests are needed to further confirm the diagnosis.2.Chinese MODY5 patients with no family history of diabetes and high glycated hemoglobin level are more likely to develop DK/DKA.Clinicians should be alert to these patients,and pay attention to early identification of DK/DKA.3.MODY patients can present with positive diabetes-related antibodies,and can develop DK/DKA due to infection,stress and other triggers on the basis of poor blood glucose control.The mechanisms are not clear,whether there are geographical differences,whether they are related to gene mutation needs further study.4.This study summarizes and analyzes the genotypes and clinical phenotypes of Chinese MODY5 patients and MODY8 patients,which will improve clinicians’ understanding of the disease.Patients with high clinical suspicion of MODY should perform genetic testing to confirm the diagnosis,regardless of positive diabetes-related antibodies,DK/DKA,or a family history of diabetes.