Contribution of Rare Large High-Penetrance CNVs to Pediatric and MODY Diabetes in Norway

Technological advancements have significantly improved our understanding of Copy Number Variants (CNVs) and their role in disease. However, detecting CNVs in clinical diagnostics remains challenging, and important pathogenic CNVs may go undetected. This study systematically assessed the impact of rare, large, high-penetrance CNVs on pediatric diabetes and Maturity-onset Diabetes of the Young (MODY) in Norway. We analyzed data from the nationwide Norwegian Childhood Diabetes Registry (NCDR) covering 2002-2018 and the Norwegian MODY Registry (NMR) from 1997-2019. CNV detection was performed using the Illumina Infinium Global Screen Array-24 v2.0 on a total of 5,889 individuals and we compared the results to diagnostic records. Our findings indicate that 0.63% of the patients in the Norwegian MODY Registry and 0.09% in the Norwegian Childhood Diabetes Registry are attributable to established pathogenic large copy number deletions detectable by array genotyping. Notably, six of the 14 pathogenic deletions identified (in the HNF1B [n=3], HNF1A [n=2], or GATA4 genes [n=1]) had not been detected through standard diagnostic methods in the routine diagnostic screening. For these individuals, accurate molecular diagnoses have significant implications for personalized treatment and follow-up. We found no evidence suggesting a major role for additional rare CNVs beyond the already established pathogenic CNVs in MODY. In conclusion, while pathogenic CNVs are rare, they remain relevant for patients of the Norwegian nationwide diabetes registries. Expanding screening for MODY variants, specifically 17q12-HNF1B and HNF1A deletions, to a larger portion of the pediatric diabetes population should be considered.