ESPE Abstracts (2018) 89 P-P1-058

Comprehensive Genetic Testing Shows One in Five Children with Diabetes and Non-Autoimmune Extra-Pancreatic Features Have Monogenic Aetiology

Kashyap A Patela, Kevin Colcloughb, Mehmet Nuri Ozbekc, Melek Yildizd, Tulay Gurane, Cemil Kocyigitf, Sezer Acarg, Zeynep Siklarh, Muge Atari, Matt B Johnsona, Sarah E Flanagana, Sian Ellarda, Filiz Mine Cizmeciogluj, Merih Berberogluh, Korcan Demirg, Gonul Catlif, Serpil Base, Teoman Akcayk, Huseyin Demirbilekl, Michael N Weedona & Andrew T Hattersleya

University of Exeter Medical School, Exeter, UK; bMolecular Genetics Department, Royal Devon and Exeter Hospital, Exeter, UK; cDiyarbakir Gazi Yasargil Eğitim ve Araştırma Hastanesi, Diyarbakır, Turkey; dKanuni Sultan Suleyman Training and Research Hospita, Istanbul, Turkey; eMarmara University Hospital, Istanbul, Turkey; fTepecik Training and Research Hospital, Izmir, Turkey; gDokuz Eylül University, Izmir, Turkey; hAnkara University School of Medicine, Ankara, Turkey; iSüleyman Demirel University, Isparta, Turkey; jKocaeil University Hospital, Izmit, Turkey; kIstinye University, Gaziosmanpasa Medical Park Hospital, Istanbul, Turkey; lHacettepe University Faculty of Medicine, Ankara, Turkey

Background/Aim: Diabetes with extra-pancreatic features in children can have a monogenic aetiology. Single gene testing is undertaken when children present with the characteristic clinical features suggestive of the underlying aetiology. We aim to assess the utility of comprehensive genetic testing for all monogenic diabetes genes in children with diabetes and any non-autoimmune extra-pancreatic features from a population with a high rate of consanguinity.

Method: We recruited 1093 children with young-onset diabetes (median age of diagnosis 8y) from 7 paediatric endocrinology centres in Turkey. All children with one or more non-autoimmune extra-pancreatic features underwent comprehensive genetic testing for 34 known monogenic diabetes genes. We generated a Type 1 Diabetes Genetic Risk Score (T1D-GRS) by genotyping 30 T1D associated single nucleotide polymorphisms. The self-reported consanguinity rate was 29.4%.

Results: 68/1093 (6.2%) children with diabetes had one or more non-autoimmune extra-pancreatic features. Comprehensive genetic testing identified 15/68 (22%) with a monogenic aetiology. In 2/15 (13%) children the identified monogenic aetiology (GCK) explained the diabetes only. In 13/15 (87%) children, the genetic aetiology explained both the diabetes and the other features. However, classical clinical features indicative of the underlying genetic aetiology were present in only 2/15 (15%) children. The remaining 11/13 (85%) children had an atypical/rare presentation of the genetic syndrome or were diagnosed with diabetes before the typical clinical features presented. Recessive mutations in WFS1 were the most common aetiology (6/15, 40%). Age of diagnosis (median 5.9y vs. 8.1y, P=0.20), duration of diabetes (4.7y vs. 3.3y, P=0.55), BMI (63rd vs. 58th centile, P=0.42) and proportion clinically reported as non-T1D (40% vs. 30%, P=0.53) was similar in children with and without a monogenic aetiology. T1D-GRS was lower in children with a monogenic aetiology compared to rest of the children (median GRS 0.23 vs. 0.27 P<0.01). Among the children with low T1D-GRS (<0.23), 41% (7/17) had monogenic diabetes compared to only 5% (1/22) with high T1D-GRS (>0.28).

Conclusion: Comprehensive genetic testing enabled early identification of syndromic forms of monogenic diabetes with minimal or an atypical presentation. All children with diabetes and any non-autoimmune extra-pancreatic features from a population with a high rate of consanguinity should be considered for comprehensive genetic testing. T1D-GRS is a novel test that helps to identify children with high probability of a monogenic aetiology.

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