About OMICS Group

1. About OMICS Group OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of making the information on Sciences and technology ‘Open Access’, OMICS Group publishes 400 online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group also organizes 300 International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions.

2. About OMICS Group Conferences OMICS Group International is a pioneer and leading science event organizer, which publishes around 400 open access journals and conducts over 300 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to credit. OMICS Group has organized 500 conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai.

3. The Importance of Making a Genetic Diagnosis in Monogenic Forms of Diabetes Daniela del Gaudio, Ph.D. Associate Director-Genetic Services Laboratory Assistant Professor-Department of Human Genetics University of Chicago

4. Diabetes Mellitus • Group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both • Chronic hyperglycemia associated with long-term damage and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels • ADA classifies diabetes into: • Type 1 (~5-10% of DM cases): predominantly in young people • Selective autoimmune destruction of the pancreatic beta cell leading to insulin deficiency • Type 2 (~90-95% of DM cases): vast majority older and overweight adults • Insulin resistance • Gestational Diabetes • Other specific types of diabetes • Rare diabetes forms of exclusively genetic origin

5. Monogenic Diabetes • 1–2% of all cases of diabetes mellitus • Caused by single-gene mutations; therefore, amenable to diagnostic testing • Mutations can arise de novo ormay be inherited • In children, almost all monogenic diabetes results from mutations in genes that regulate β-cell function and infrequently from mutations resulting in very severe insulin resistance • Often misdiagnosed as T1DM or even T2DM

6. Phenotypes of Monogenic Diabetes Monogenic Diabetes Neonatal MODY Diabetes with extrapancreatic features HNF1A (very frequent) **GCK (very frequent) HNF4A (frequent) HNF1B (frequent) PDX1 NEUROD1 KLF11 CEL PAX4 INS BLK More recently: ABCC8 KCNJ11 Insulin resistance + Diarrhea and/or pancreatic insufficiency +Kidney/skeletal/ visual/deafness Transient Permanent INSR AGPAT2 BSCL2 CAV1 PTRF LMNA PPARG ZMPSTE24 AKT2 CIDEC NEUROG3 FOXP3 PDX1 PTF1A RFX6 GLIS3 + Neurodev disability HNF1B GLIS3 EIF2AK3 SLC2A2 PAX6 WS1 SLC19A2 NEUROD1 6q24 abnormalities(>70%) -Paternal UPD6 (~40%) -paternal dup of 6q24 (~30%) -maternal hypomethylation (~30%) ABCC8, KCNJ11 (~25%) HNF1B, INS (rare) KCNJ11 (~30%) ABCC8 (~19%) INS (~20%) GCK (~4%) PDX1<1% KCNJ11 ABCC8 EIF2AK3 GLIS3 NEUROD1 PTF1A PAX6 IER3IP1 ** does not need treatment! Greeley et al. CurrDiab Rep 2011 Molven & Njolstad. Expert Rev MolDiagn. 2011 Temple & Shield. Rev EndocrMetabDisord 2010

7. Regulation of Insulin Secretion Fajans and Bell NEJM 2001

8. The KATP Channel in β –cells ABCC8 KCNJ11 SperlingNEJM 2006

9. Mutated KATP Channel Closes with Sulfonylurea Pearson et al. NEJM 2006

10. Why Diagnose Monogenic Diabetes? Gene Mutation Identification Implications for other family members Establish a Diagnosis Explain other associated features Correct diagnosis and treatment Allow appropriate genetic counseling Predict clinical course Treatment

11. Defining Genetic Etiology Can Alter Treatment MODY Syndromic forms Neonatal Diabetes Familial, mild fasting hyperglycemia Transient Permanent Test for GCK heterozygous mutations Test for HNF1A, if negative HNF4A Depending on which gene is mutated Test for 6q24 abnor If negative: KCNJ11/ABCC8 Test for KCNJ11 and if negative, ABCC8 Positive: oral sulfonylurea Positive: No treatment Insulin or Sulfonylurea If NEG: test INS/GCK or other rare causes Transient insulin Positive: oral sulfonylurea Adapted from Murphy et al. Nat ClinPractEndocrinol Metab.2008

12. Genetic Testing for Monogenic Diabetes • Currently available genetic testing for monogenic diabetes is primarily based on Sanger sequencing of multiple genes in a sequential manner, which is time consuming and potentially costly, and limits the diagnosis to a few selected genes • Choice of genes to be tested relies on the availability of reliable clinical information, although such features may be subclinical • Clinical laboratories now developing NGS based targeted gene panels to test for genetically heterogeneous conditions • UofC Monogenic Diabetes Testing

13. Targeted NGS Panel for Monogenic Diabetes at UofC +

14. Gene Selection—NDM/MODY Panel • 32 genes: • NDM/MODY/HI (KCNJ11, ABCC8, INS, PDX1, NEUROD1, KLF11, CEL, PAX4, BLK, GATA6, PTF1A, RFX6, ZFP57, GLIS3, EIF2AK3, NEUROG3, INSR, SLC2A2, IER3IP1, WFS1, CISD2, FOXP3, AKT2, GLUD1, HADH, CP) • Rare syndromic diabetes: ALMS1, DCAF17, SLC29A3, PAX6, SLC19A2 - Haloplex enrichment, IlluminaMiSeq sequencing - Clinically validated on 19 controls with known mutations Neonatal Diabetes/Maturity-Onset Diabetes of The Young

15. Panel Validation-Detection of Known Mutations

16. Clinical Utility of the DM Targeted Panel 76 samples 34 (45%) previously tested 42 (55%) previously not tested Neonatal 23 (68%) MODY 11 (32%) Neonatal 9 (22%) MODY 33 (78%) 3 (13%) 0 (0%) 4 (44%) 12 (36%) POSITIVES 3 (9%) 16 (38%) 19 (25%) Neonatal: 7 positives (22%) – MODY: 12 positives (27%)

17. Pathogenic Sequences Identified in This Study ^ Novel to this study

18. Pathogenic Sequences Identified in This Study • Genetic results may allow transition to more appropriate drug therapy or discontinuation of drug therapy. • Patients and families benefit from having information on the predicted clinical course and familial risk, and receive genetic counseling.

19. Pathogenic Sequences Identified in This Study

20. EIF2AK3 Patient • 3 years old male diagnosed with DM at 3 months of age • Treated with insulin • Parents both from Mexico, denied consanguinity • Previous Testing Negative • KCNJ11/INS/6q24/PDX1/ABCC8 • Testing on the NGS Panel revealed a homozygous c.2758C>T (p.Gln920*) mutation in EIF2AK3 • Gene associated with Wolcott-Rallison syndrome • EIF2AK3 was not suspected because consanguinity, delayed growth, abnormal bone development and hepatic complications had not been reported • Demonstrate the limitations of the candidate gene approach in that the diagnosis of some forms of monogenic diabetes is not always clear-cut and may be complicated by incomplete or absent clinical and/or family history information WT Pt EIF2AK3: c.2758C>T (p.Gln920*)

21. Conclusions • The children with the INS mutations, the homozygous GCK mutation and the EIF2AK3 mutation will probably not benefit from a therapy point of view. However, the diagnosis will clearly be of value from a family planning and prognostic standpoint • The other 15 families (9 GCK, 2 HNF1A, 1 ABCC8 and 2 KCNJ11) will benefit enormously • The GCK families (some are huge pedigrees) may come off of all therapy or have their therapy personalized

22. Molecular Medicine Comes To The Rescue Targeted therapy turns life around for child with neonatal diabetes Lilly Jaffe, of Chicago, was diagnosed with T1DM at the age of one month. She received multiple daily insulin injections before getting on an insulin pump. In summer 2006 genetic testing confirmed Lilly was one of those individuals misdisdiagnosed with T1DM. Instead she had monogenic diabetes. She was admitted to the University of Chicago’s Clinical Research Center where she began a week-long program to see if the oral treatment could work for her. After 1 week, Lilly had begun to produce her own insulin, well on her way to insulin independence and ready to get in a few days of beach time in Michigan before starting first grade http://www.uchospitals.edu/news/2006/20060911-diabetes.html

23. Yu-Wei Cheng, PhD GorkaAlkorta-Aramburu, PhD Viswateja Nelakuditi, MS Soma Das, PhD Siri Greeley, MD, PhD David Carmody, MD Jazzmyne Dickens, BS Lou Philipson, MD, PhD Graeme Bell, PhD

24. Haloplex Target Enrichment of Exons and Flanking Intronic Sequences Digestion Hybridization Capture Amplification

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