Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
| Autor: | Xiao Fan, Wendy K. Chung, Emily Breidbart, Rudolph L. Leibel, Jiancheng Guo, Patricia Lanzano, Charles A. LeDuc, Liyong Deng |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male 0301 basic medicine Proband medicine.medical_specialty Endocrinology Diabetes and Metabolism New York 030209 endocrinology & metabolism Article Maturity onset diabetes of the young Germinal Center Kinases Cohort Studies Young Adult 03 medical and health sciences 0302 clinical medicine Endocrinology Molecular genetics Exome Sequencing Humans Medicine Genetic Testing Hepatocyte Nuclear Factor 1-alpha Registries Exome sequencing Genetic testing Genetics medicine.diagnostic_test business.industry Prognosis medicine.disease HNF1B HNF1A Phenotype 030104 developmental biology Diabetes Mellitus Type 2 Mutation Pediatrics Perinatology and Child Health Female Age of onset business Biomarkers Follow-Up Studies |
| Zdroj: | J Pediatr Endocrinol Metab |
| ISSN: | 2191-0251 0334-018X 2020-0501 |
| DOI: | 10.1515/jpem-2020-0501 |
| Popis: | Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband. |
| Databáze: | OpenAIRE |
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