Sílvia Santos Monteiro1, Tiago da Silva Santos2, Liliana Fonseca2, Guilherme Assunção2, Ana M Lopes2, Diana B Duarte2, Ana Rita Soares3, Francisco Laranjeira4,5, Isaura Ribeiro4,5, Eugénia Pinto4, Sónia Rocha4, Sofia Barbosa Gouveia6, María Eugenia Vazquez-Mosquera6, Maria João Oliveira7, Teresa Borges7, Maria Helena Cardoso2. 1. Division of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário do Porto, Largo Professor Abel Salazar, 4099-001, Porto, Portugal. silviamsmonteiro@hotmail.com. 2. Division of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário do Porto, Largo Professor Abel Salazar, 4099-001, Porto, Portugal. 3. Division of Medical Genetics, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário do Porto, Porto, Portugal. 4. Division of Genetic Biochemistry. Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário do Porto, Porto, Portugal. 5. Unit for Multidisciplinar Biomedical Research (UMIB), Instituto de Ciências Biomédicas Abel Salazar. Universidade do Porto, Porto, Portugal. 6. University Clinical Hospital of Santiago de Compostela. IDIS, CIBERER, MetabERN, 15701, Santiago de Compostela, Spain. 7. Division of Pediatric Endocrinology. Department of Pediatrics. Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal.
Abstract
AIMS: Monogenic forms of diabetes that develop with autosomal dominant inheritance are classically aggregated in the Maturity-Onset Diabetes of the Young (MODY) categories. Despite increasing awareness, its true prevalence remains largely underestimated. We describe a Portuguese cohort of individuals with suspected monogenic diabetes who were genetically evaluated for MODY-causing genes. METHODS: This single-center retrospective cohort study enrolled patients with positive genetic testing for MODY between 2015 and 2021. Automatic sequencing and, in case of initial negative results, next-generation sequencing were performed. Their clinical and molecular characteristics were described. RESULTS: Eighty individuals were included, 55 with likely pathogenic/pathogenic variants in one of the MODY genes and 25 MODY-positive family members, identified by cascade genetic testing. The median age at diabetes diagnosis was 23 years, with a median HbA1c of 6.5%. The most frequently mutated genes were identified in HNF1A (40%), GCK (34%) and HNF4A (13%), followed by PDX1, HNF1B, INS, KCNJ11 and APPL1. Thirty-six unique variants were found (29 missense and 7 frameshift variants), of which ten (28%) were novel. CONCLUSIONS: Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of its subtypes, leading to more personalized treatment and follow-up strategies.
AIMS: Monogenic forms of diabetes that develop with autosomal dominant inheritance are classically aggregated in the Maturity-Onset Diabetes of the Young (MODY) categories. Despite increasing awareness, its true prevalence remains largely underestimated. We describe a Portuguese cohort of individuals with suspected monogenic diabetes who were genetically evaluated for MODY-causing genes. METHODS: This single-center retrospective cohort study enrolled patients with positive genetic testing for MODY between 2015 and 2021. Automatic sequencing and, in case of initial negative results, next-generation sequencing were performed. Their clinical and molecular characteristics were described. RESULTS: Eighty individuals were included, 55 with likely pathogenic/pathogenic variants in one of the MODY genes and 25 MODY-positive family members, identified by cascade genetic testing. The median age at diabetes diagnosis was 23 years, with a median HbA1c of 6.5%. The most frequently mutated genes were identified in HNF1A (40%), GCK (34%) and HNF4A (13%), followed by PDX1, HNF1B, INS, KCNJ11 and APPL1. Thirty-six unique variants were found (29 missense and 7 frameshift variants), of which ten (28%) were novel. CONCLUSIONS: Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of its subtypes, leading to more personalized treatment and follow-up strategies.
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