Next Generation Sequencing Analysis of MODY-X Patients: A Case Report Series

Abstract

Background: Classic criteria for a maturity-onset diabetes of the young (MODY) diagnosis are often unable to identify all subjects, and traditional Sanger sequencing, using a candidate gene approach, leads to a high prevalence of missed genetic diagnosis, classified as MODY-X. Next generation sequencing (NGS) panels provide a highly sensitive method even for rare forms. Methods: We investigated 28 pediatric subjects suspected for MODY-X, utilizing a 15-gene NGS panel for monogenic diabetes (MD). Results: NGS detected variants of uncertain significance (VUS), likely pathogenic or pathogenic for rarer subtypes of MODY, in six patients. We found variants in the wolframin gene (WFS1), traditionally not considered in MD genetic screening panels, in three patients; KCNJ11 gene mutation, typically responsible for neonatal diabetes and rarely causing isolated diabetes in adolescents; INS gene mutation; a variant in the HNF1B gene in a young male with diabetes on sulfonylurea treatment. Conclusion: In our cohort, the availability of an NGS panel for MD was determined for the correct identification of MD subtypes in six patients with MODY-X. Our study underlines how a precise diagnosis utilizing NGS may have an impact on the management of different forms of MODY and, thus, lead to a tailored treatment and enable genetic counselling of other family members.

Special Issue—Diabetes Mellitus: Current Research and Future Perspectives

“…However, the classic clinical criteria for MODY diagnosis are often unable to identify all subjects, and using a candidate gene approach leads to missing genetic diagnosis. Therefore, this study sustains the importance of using next-generation sequencing (NGS) panels as a highly sensitive method even for rare forms of monogenic diabetes [4].…”

Family and Community Nurses as a Resource for the Inclusion of Youths with Type 1 Diabetes at School

“…The strengths of this study are as follows: (i) we developed a model starting from actors’ needs and suggestions, which should be tailored on the basis of students’ age, individual level of self-management, and acceptance of the disease according to a precision medicine-based approach [ 30 , 31 , 32 ]; and (ii) this model is more sustainable in our reality compared with one involving school nurses and complies with the indications of the PNRR.…”

Moody Only Monogenic? A Narrative Review of the Rare and Low-Penetrant Genetic Variants

“…(64,65) In particular, after the first genetic mutations identified in the 1990s regarding GCK (MODY 2), HFN1A (MODY 3) and HFN14A (MODY 1), the development of DNA sequencing methods has significantly enhanced the exploration of novel causal variants. (5,66,67,68,69,70) Sanger sequencing represents the conventional genetic testing for single-gene genetic disorders, leading, however, to a relevant rate of unclear MODY diagnosis (also known as MODY-X) ranging from 46.2-73.9%. (70) Unlike the candidate gene approach of the Sanger method, the advent of Next-Generation Sequencing (NGS) technologies, such as whole genome, exome and targeted sequencing, currently offer a pivotal role in providing valuable insights into the genetic architecture of MODY.…”

“…(5,66,67,68,69,70) Sanger sequencing represents the conventional genetic testing for single-gene genetic disorders, leading, however, to a relevant rate of unclear MODY diagnosis (also known as MODY-X) ranging from 46.2-73.9%. (70) Unlike the candidate gene approach of the Sanger method, the advent of Next-Generation Sequencing (NGS) technologies, such as whole genome, exome and targeted sequencing, currently offer a pivotal role in providing valuable insights into the genetic architecture of MODY. By providing a highly sensitive and specific technique, NGS enables the detection of both common and rare pathogenetic variants associated with the maturity-onset diabetes of the young.…”

“…By providing a highly sensitive and specific technique, NGS enables the detection of both common and rare pathogenetic variants associated with the maturity-onset diabetes of the young. (70) Additionally, the efficacy of NGS is also highlighted by its accelerated turnaround time of comprehensive genetic profiling, which has expedited the diagnostic algorithm, enabling subsequently a prompt and tailored clinical management of the patient. In the era of precision medicine NGS affordability, however, differs widely among diverse socio-geographical settings also due to financial considerations.…”