Application of an extended NGS gene panel in 573 monogenic diabetes mellitus referrals

Anny Mertzanian; Irene Fylaktou; Ioanna Farakla; Michaela Nikolaou; Maria Dolianiti; Sophia Sakka; Vasilakis Ioannis Anargyros; Gantenbein Christina Kanaka; Amalia Sertedaki

doi:10.1530/endoabs.110.P443

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Endocrine Abstracts (2025) 110 P443 | DOI: 10.1530/endoabs.110.P443

ECEESPE2025 Poster Presentations Diabetes and Insulin (143 abstracts)

Application of an extended NGS gene panel in 573 monogenic diabetes mellitus referrals

Anny Mertzanian ¹ , Irene Fylaktou ¹ , Ioanna Farakla ¹ , Michaela Nikolaou ¹ , Maria Dolianiti ¹ , Sophia Sakka ¹ , Ioannis Anargyros Vasilakis ¹ , Christina Kanaka Gantenbein ¹ & Amalia Sertedaki ¹

Author affiliations

¹Division of Endocrinology, Diabetes and Metabolism, “Aghia Sophia» Children’s Hospital ENDO-ERN Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece

JOINT2698

Introduction: Monogenic Diabetes (MD) constitutes a genetically and clinically distinct group of diabetes mellitus (DM) that includes Maturity Onset Diabetes of the Young (MODY), Neonatal Diabetes Mellitus (NDM) and Syndromic DM. The utilization of Next Generation Sequencing (NGS) with extended gene panels in the diagnostic routine of patients with suspected MD, gives the opportunity to identify rare MODY subtypes and syndromic forms of MD.

Patients and Methods: Genetic analysis was performed in 573 Greek unrelated patients with clinical suspicion of monogenic diabetes beyond infancy. A targeted gene panel (tNGS) was designed including originally the genes GCK, HNF1A, HNF4A, HNF1B, INS, ABCC8, KCNJ11, NEUROD1, PDX1 whereas the genes INSR, WFS1 and CEL were added later. All referrals were tested for the original panel and 421 for the extended. Confirmation of the detected variants and segregation analysis was performed employing Sanger Sequencing. For the identification of the MT-TL1 m. 3243A>G variant, Sanger sequencing was carried out in 3 different tissues derived from 2 patients (peripheral blood, urine, buccal swab) to evaluate varying levels of heteroplasmy.

Results: Out of 573 tested patients, 167 were found to carry variants in genes associated with frequent and rare MODY subtypes alongside syndromic forms of MD. As expected, the most frequent MODY subtypes were GCK (67/573) and HNF1A (39/573) followed by ABCC8 (18/573), HNF4A (8/573) and HNF1B (8/573). We identified 9/573 patients with heterozygous variants in rare MODY genes, KCNJ11(n = 5) and INS (n = 4). Variants in syndromic genes were identified in 18/423 patients: WFS1 (n = 12), INSR (n = 2), CEL (n = 3), MT-TL1 m. 3243A>G (n = 1), most of the patients presenting with diabetes only (Table 1).

Table 1: Patients with variants in syndromic genes
Genes	No. Patients	Zygosity	Extra-pancreatic/Syndromic features
CEL	3	heterozygous	Pancreatic exocrine dysfunction (n = 1)
INSR	2	heterozygous	Hyperinsulinemia (n = 1), Hypertriglyceridemia (n = 1)
WFS1	12	9 heterozygous	Family history of vision loss (n = 1)
		2 compound-heterozygous	Bilateral nuclear cataract (n = 1)
		1 homozygous	Optic atrophy+deafness
MT-TL1 m. 3243A>G	1	heteroplasmic	hearing loss+myopathy+ gastrointestinal problems

Discussion: In our cohort, frequent MODY subtypes were identified in 24. 4% of tested patients and rare MODY subtypes in 1. 6%. Variants in syndromic monogenic diabetes genes were identified in 4. 2% of the referrals. Multiple gene screening in MD patients, through expanded gene panels even in patients lacking typical features, provides early diagnosis of potential comorbidities, diseases progression prognosis and family genetic counseling.