NGS no diagnóstico da diabetes MODY

Abstract

[Resumo] A diabetes MODY é una enfermidade monoxénica pouco frecuente dentro de todos os casos de diabetes, que se caracteriza por una progresiva disfunción nas células β- pancreáticas, por ser independente de insulina e comezar a desenvolverse en idades moi tempranas. Un diagnóstico molecular pode chegar a supoñer un cambio de tratamento nun paciente, un diagnóstico precoz ou un seguimento efectivo da progresión da enfermidade. Existen unha serie de xenes implicados na diabetes MODY e diversas institucións están identificando variantes relacionadas con esta patoloxía a través da secuenciación dun panel de xenes mediante NGS (Next Generation Sequencing). A NGS está afianzándose na xenética clínica pois permite a realización de diagnóstico molecular a varios pacientes simultaneamente e en moi pouco tempo. Para este traballo foron seleccionados once pacientes baixo os criterios do Complexo Hospitalario Universitario de A Coruña para a realización dun diagnóstico molecular para diabetes MODY. Este consistiu na secuenciación dun panel de xenes relacionados coa mesma (ABCC8, GCK, HNF1A, HNF1B, HNF4A, KCJ11, INS) mediante tecnoloxía NGS. Deste xeito foi realizada unha posta a punto da técnica para a elaboración dun Protocolo Normalizado de Traballo (PNT) que se utilizará rutinariamente no laboratorio e unha análise preliminar das variantes obtidas. Atopáronse variantes de interese clínico en cinco dos once pacientes (unha patolóxica, dúas probablemente patolóxicas e catro de significado incerto), as cales serán estudadas posteriormente e confirmadas mediante secuenciación Sanger. A posterior integración desta información será clave para complementar o diagnóstico clínico de cada paciente.

[Abstract] Maturity-onset diabetes of the young (MODY) is a monogenic disorder with a low frequency amongst all diabetes cases. Some of the characteristics features of MODY are the progressive pancreatic β-cell dysfunction, as well as non-insulin dependence, and early-onset diabetes. A molecular diagnosis may imply a change in the treatment, an early diagnosis or a better management of the clinical course of this disease. Several genes are associated with MODY. Some institutions are currently performing variant detection using a gene panel, one of the applications of the NGS (Next Generation Sequencing) technology. NGS technologies have enabled a dramatic transformation in clinical genetics, as they allow molecular diagnoses for many patients at once and in a short time. Following the criteria established by the Complexo Hospitalario Universitario de A Coruña, eleven patients were selected to participate in a molecular diagnosis of MODY. For this, we sequenced a gene panel (ABCC8, GCK, HNF1A, HNF1B, HNF4A, KCJ11, INS) using NGS technology. As a result of this pilot study, we set up a Standard Operating Procedure (SOP), which will be used as a routine in this laboratory. Additionally, we proceeded with a preliminary variant analysis. Clinically relevant variants were found in five out of eleven patients: one pathogenic, two likely pathogenic and four variants of uncertain significance. All of them will be studied and validated by Sanger sequencing. The subsequent integration of this information will be key to complement the clinic diagnosis of each patient.