September 30, 2022

Monogenic diabetes clinic (MDC): 3-year experience

Novella Rapini, Patrizia I. Patera, Riccardo Schiaffini, Paolo Ciampalini, Valentina Pampanini, Matteoli M. Cristina, Annalisa Deodati, Giorgia Bracaglia, Ottavia Porzio, Rosario Ruta, Antonio Novelli, Mafalda Mucciolo, Stefano Cianfarani, Fabrizio Barbetti

The most common cause of diabetes in children is polygenic autoimmune type 1 diabetes mellitus (T1DM); however, a significant proportion of patients in clinics have a single-gene pathogenic variation, which is suggestive of monogenic diabetes mellitus (MDM). The rapidly expanding field of MDM encompasses both common non-syndromic and rare syndromic subtypes, including genetic forms involving chromosome 6 aberrations and mitochondrial DNA mutations. With the use of next-generation sequencing, simultaneous screening of all MDM genes enables improved genetic diagnoses. This publication covers the first three years of the Monogenic Diabetes Clinic’s (MDC) efforts to optimize genetic testing for patients suspected of having a monogenic form of diabetes.


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Genetic testing eligibility required negative results for four T1DM-related autoantibodies, diabetes, or impaired fasting glucose (IFG) diagnosis. The majority of individuals with IFG plasma levels ≥ 100–125 mg/dl had an oral glucose tolerance test carried out. In situations where family history indicated autosomal dominant inheritance, testing took into account diabetes cases with onset after age 25. Lean patients with severe insulin resistance were screened for insulin receptor genetic changes. Referrals to the MDC came from diverse sources, including external hospitals, and self-referrals.


Utilizing the Twist Custom Panel kit, 8245 genes were subjected to clinical exome sequencing (CES) on genomic DNA. The Geneyx Analysis platform (Geneyx Genomex) was used to annotate variants and prioritize potential genes depending on the patient’s phenotype. An analysis was done on a “virtual panel” of genes linked to diabetes. Protein-changing, rare recessive homozygous, compound heterozygous, and pathogenic or probably pathogenic heterozygous variations were found using data filtering. Sanger sequencing was used to confirm potential causal variations, and variant classification followed ACMG/AMP criteria. Patients with CES-negative newborn diabetes mellitus underwent MS-MLPA analysis for 6q24 aberrations. Probands or guardians received explanations of the reports, and for new variants in rare genes, scientists had discussions with the Monogenic Diabetes Variant Curation Expert Panel.


The MDC evaluated 68 cases through CES after receiving 97 patient referrals over a three-year period, four of which were from outside of Europe. In 45.5% of the patients, CES found causal variations. Patients were divided into two groups for the study: Group 1 examined patients whose hyperglycemia was reported after the age of one year and found causal variations in genes including GCK, HNF1A, and HNF1B. In the group of neonatal diabetic mellitus patients (NDM; Group 2), the authors reported variations in genes such as KCNJ11, ABCC8, and PDX1 that were either pathogenic or likely pathogenic. This paper provides insights into customized treatment options and emphasizes the critical significance that genetic diagnosis plays in directing therapeutic decisions for monogenic diabetes.


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