A Family Study With Genetic Screening On The Maturity Onset Diabetes Of The Young (MODY) In Two Adolescents

BackgroundDiabetes mellitus(DM)is a group of metabolic diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion and/or action.The number of people suffering from diabetes is globally increasing and is already one of the most common diseases in the world.The prevalence of diabetes in China is estimated up to 92.4million to 119million which makes China one of the world's leading countries with high prevalence of diabetes.Diabetes in children is also increasing,and more morechildren with diabetes are found to beinsulin independent and different from typical type 1 and type 2.Maturity-onset diabetes of the young(MODY)is an autosomal dominant form of diabetes typically occurring at young age.MODY is a rare monogenic form of diabetes resulting from mutations in a single gene which results in dysfunction of ? cell in pancreas leading toward primary insulin secretion defects.Most of MODY cases are caused by mutations in 14 genes.Genetic analysis is the primary method of MODY research.Depending on types of genes with mutation,pathogenesis,clinical manifestation and treatment can differ.Aim/hypothesisThe aim of this thesis is to diagnose and proceed further on genetic testing for two patients highly suspected with MODY based on clinical features.MODY causes numerous clinical manifestations.It mostly relies on genetic screening in order to clearly diagnose MODY and to identify the specific pathogenic gene with mutation.MODY has a strong family inheritance.Genetic screening offers a higher likelihood of determining if a family member has a MODY gene mutation,enabling a more accurate analysis of the condition to be made.A genetic diagnosis can result in identifying the specific pathogenic gene which is mutated and can lead to a more individualized treatment with better effect.Materials and methodsOne of the two probandswas 12 years old female.She had recently been diagnosed for diabetes and has 3 generations of family history of diabetes.She was highly suspected to have MODY;the other probandwas a 19 years old male.He had 7 years history of diabetes and a family history of diabetes.To identify the pathogenic gene,we used clinical data from the probands(including physical examination,laboratory examination and imaging results).First we proceeded with a target area capture on the proband and the family member diagnosed with diabetes.Then we proceeded with target area capture Next Generation Sequencing(NGC)technology.This screens the existence of quilt genes and the same gene mutation.ResultsRare gene mutation was found from two families of the patients.According to other researches of mutation site,protein function prediction,and gene function,two genes were found to be most likely to be related to MODY:CACNB3 and CEL.CACNB3 gene encodes a regulatory beta subunit of the voltage-dependent calcium channel.This gene also contributes to the regulation of the surface expression and gating of calcium channels and may also play a role in the regulation transcription factors and calcium transport.CEL gene is related with MODY8(early-onset type diabetes type 8),pancreatitis,lipoprotein metabolism and the mutation of MODY8 associates with diarrhea and pancreatic exocrine dysfunction caused by hyperglycemia.With our probands,mutation has occurred but there was no pancreatic dysfunction.Therefore the mutation and diabetes is not necessarily related.ConclusionMutation in CACNB3 and CEL genes were found,but further studies need to be undertake to find if these two gene were subtypes of rare types of MODY.