ESPE Abstracts (2018) 89 P-P1-049

Life Changing Decisions due to Etiological Genetic Diagnosis in Families of Children with Maturity Onset Diabetes of the Young (MODY)

Gherta Brila, Martine Vaxillaireb, Noah Grubera,c, Kineret Mazor-Aronovitcha,c, Michal Ben-Amia,c, Rachel Frumkin Ben-Davida, Yonathan Yeshayahua,c, Olivier Sandb, Amelie Bonnefondb, Philippe Froguelb,d & Orit Pinhas-Hamiela,c

aPediatric Endocrine and Diabetes Unit, Edmond and Lili Safra Children’s Hospital, Sheba Medical Center, Ramat-Gan, Israel; bCNRS UMR 8199, Integrative Genomics and Modelling of Metabolic Diseases, University of Lille, European Genomics Institute of Diabetes, F-59000, Lille, France; cSackler school of Medicine Tel-Aviv University, Tel-Aviv, Israel; dGenomics of Common Disease, Imperial College London, London, UK

Background: Maturity Onset Diabetes of the Young (MODY) is a heterogeneous group of disorders characterized by pancreatic beta-cell dysfunction, and usually referred to monogenic forms of diabetes mellitus to distinguish them from the more common type 1 (T1D) or type 2 diabetes (T2D). Fourteen different MODY genetic subtypes have been identified so far. Making a definite diagnosis is very challenging because of overlapping clinical phenotypes between diabetes subtypes. Nevertheless, distinction within childhood diabetes spectrum is crucial as optimal treatments are different, with the possibility of treating some MODY subtypes with oral agents and some can even be managed without medication. Accurate diagnosis is significant to probands as well as to other family members. It is estimated that up to 1–2% of those diagnosed with gestational diabetes, T1D or T2D have MODY.

Patients and methods: We established a collaboration between the pediatric endocrinology clinic in Safra Children’s Hospital and the Integrative Genomics and Modelling of Metabolic Diseases research laboratory at EGID (Lille). Sixteen probands with suspected MODY based on clinical evaluation were rigorously selected for a comprehensive genetic analysis of all known monogenic diabetes genes using next-generation sequencing and Illumina HiSeq equipment (LIGAN-PM platform at EGID, Lille, France). After human genome alignment, quality controls and variant calling, candidate rare mutations were fully annotated and filtered, and criteria for mutation pathogenicity from the American College of Medical Genetics guidelines were used to score the identified mutations as pathogenic or likely pathogenic for MODY.

Results: The genetic diagnosis rate in the clinically suspected MODY patients was 68.7%. In 10 patients, we identified pathogenic/likely pathogenic mutations in GCK (7 cases), HNF1A (2 cases), APPL1 (one case with a nonsense mutation) and in WFS1 (one case with a homozygous mutation). The WFS1 missense mutation was previously reported in four cases, 2 of them presenting signs of Wolfram syndrome and one with monogenic diabetes. As a result of the genetic confirmation of MODY mutation, insulin treatment was withheld in two children; in 4 adults insulin treatment was discontinued, (one of them was on insulin pump); and antidiabetic oral medication was discontinued in one adult. Genetic counseling was given to family members.

Conclusion: Our study confirms that a comprehensive NGS analysis guided by a thorough clinical evaluation is an accurate powerful approach to make a precision diagnosis in monogenic diabetes. Distinction between monogenic diabetes and other forms of diabetes enabled us to individualize an adequate treatment.