ESPE Abstracts (2022) 95 P1-247

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1Dipartimento Pediatrico Universitario Ospedaliero, IRCCS “Bambino Gesù” Children’s Hospital, Rome, Italy; 2Clinical Biochemistry Laboratory, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy; 3Genetics and Rare Disease Research Division, Bambino Gesù Pediatric Hospital, Rome, Italy; 4Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 5Department of Women's and Children's Health, Karolinska Institute and University Hospital, Stockholm, Sweden


Background: In Italy monogenic forms of hyperglycemia account for more than 6% of cases referred to pediatric diabetes clinics. In January 2019 we started a Monogenic Diabetes Clinic (MDC) with the three main aims: a) implementing a standardized pathway towards genetic testing, 2) ease the revision of complex cases, 3) implement standardized therapies for monogenic diabetes mellitus (MDM) subtypes.

Methods: Type 1 diabetes-related autoantibodies were tested by ELISA. DNA analysis was performed by NovaSeq6000 platform. Forty-two MDM genes were analyzed, including rare recessive subtypes. Chromosome 6 aberrations were analysed by MLPA. Genetic variants were classified into 5 categories; only variants classified as likely pathogenic (LP), pathogenic (P) or variant of uncertain significance (VUS) were considered.

Results: A total of 102 incident, T1DM autoantibodies negative patients with hyperglycemia were referred during the Jan 2019-Dec 2021 period. No genetic analysis was requested for 12 patients and DNA was not available for 9 patients at the time of writing. We analyzed reports of genetic testing obtained in 60 patients until June 2021. Forty-seven patients were referred to investigate the origin of impaired fasting glucose or diabetes with onset beyond 1 year of age (Group 1). Eight incident cases were diagnosed with Neonatal Diabetes Mellitus (NDM; Group 2). Two lean female patients with fasting hyperinsulinism and post-load hyperglycemia were diagnosed as type A severe insulin resistance (Type A SIR). A pathogenic or likely pathogenic variant of GCK, HNF1A and HNF1B were identified in 10, 4 and 1 patients of Group 1, respectively. A large deletion of chromosome 17q12 encompassing HNF1B was also identified. Biallelic SLC2A2 gene (Fanconi-Bickel s.) variants were detected in 1 patient. VUS in KCNJ11, ABCC8, and PDX1 (two) were identified in 4 patients, while 26 were negative to the genetic testing. In Group 2 a pathogenic or likely pathogenic variant was identified in KCNJ11 (3 variants), ABCC8 (1 variant) and PDX1 (biallelic variants); a VUS in ABCC8 was detected. In one patient a 6q24 methylation defect was found. Heterozygous pathogenic variants in the INSR were identified in patients with Type A SIR. If we consider also VUS, pick-up rate was 44.6% and 87% for Group 1 and Group 2, respectively. When 14 patients with normoglycemic parents were excluded, pick-up rate for Group 1 increased to 63.6% (21/33). We conclude that including patients with no parental history of hyperglycemia decreases the pick-up rate of "common" autosomal dominant forms of MDM.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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