Exome Sequencing and the Genetics of Diabetes German Exome Sequencing.pdf13 Severe insulin...
Transcript of Exome Sequencing and the Genetics of Diabetes German Exome Sequencing.pdf13 Severe insulin...
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Michael German, MDUCSF Diabetes Center
Exome Sequencingand the
Genetics of Diabetes
Age-Adjusted Prevalence of Diagnosed Diabetes Among US Adults
<4.5% Missing data 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% ≥9.0%
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
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CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics
Number and Percentage of U.S. Population with Diagnosed Diabetes, 1958-2013
Diabetes in the US
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Diabetes: GeneticsConcordance Rates in Identical Twins:
Type 1 Diabetes: ~40%.
Type 2 Diabetes: ~90%.
Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk
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Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk2. Insulin Gene
Type 1 Diabetes Genes1. MHC Locus >50% of genetic risk2. Insulin Gene3. Others
Mehers, K. L. et al. Br Med Bull 2008 88:115-129; doi:10.1093/bmb/ldn045
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Type 2 Diabetes:The Search for Genes
• Although type 2 diabetes runs in families, the inheritance in most families is complex.
• Currently, family history remains the most valuable genetic test.
Types of Diabetes
German, M.S., and Masharani, U. (2011). Pancreatic Hormones and Diabetes Mellitus. In Greenspan's Basic & Clinical Endocrinology. D.G. Gardner, D.M. Shoback, and F.S. Greenspan, eds. (New York: McGraw-Hill Medical), pp. 573-655.
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Types of Diabetes
1. Type 1 diabetes.
2. Type 2 diabetes.
3. Monogenic Diabetes.
4. Secondary Diabetes.
5. Gestational Diabetes (GDM).
1/200
1/12
1/200
1/200
1/6 pregnancies
Diabetes: GeneticsMonogenic Diabetes
• Maturity Onset Diabetes of the Young (MODY)
• Neonatal Diabetes (TNDM & PNDM)• Mitochondrial Diabetes• Rare forms of severe insulin resistance• Syndromic Diabetes
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MODY: Maturity Onset Diabetes of the Young
• Autosomal dominant inheritance pattern. --Every generation, 50%• Onset commonly before age 25.
• Not obese.• Islet autoantibodies negative.
MODY2: GCK Glucokinase
• Combined β-cell and liver defect.Impaired insulin secretion in response to glucose.
• Moderate hyperglycemia.• No disease progression.• Low incidence of complications.
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MODY3: HNF1A/TCF1
RNApolymerase
HNF1A
MODY3: HNF1A• β-cell defect.
Impaired insulin secretion.
• Severe hyperglycemia.• Disease progression.• High incidence of complications.• Very sensitive to sulfonylureas.• Low renal glucose threshold.
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MODY Genes
MODY1: HNF4AMODY2: GCKMODY3: HNF1A / TCF1
MODY5: HNF1B / TCF2
MODY5: HNF1B• β-cell defect.
Impaired insulin secretion.• Severe hyperglycemia.• Disease progression.• High incidence of complications.• Congenital renal defects.• Hypomagnesemia.• Hypoplastic pancreas.• Rarely presents as Neonatal Diabetes.
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MODY GenesMODY1: HNF4AMODY2: GCKMODY3: HNF1A / TCF1MODY4: PDX1 / IPF1MODY5: HNF1B / TCF2MODY6: NEUROD1MODY7: KLF11
MODY GenesMODY1: HNF4AMODY2: GCKMODY3: HNF1A / TCF1MODY4: PDX1 / IPF1MODY5: HNF1B / TCF2MODY6: NEUROD1MODY7: KLF11MODY8: CELMODY9: PAX4MODY10: INSMODY11: BLK
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Diabetes: Genetics
Neonatal Diabetes
• Onset before age 6 months.• TNDM Transient (<1 year). • PNDM Permanent.
Neonatal DiabetesTransient: 6q24 (paternal isodisomy)Transient: ZFP57 (recessive)Trans/Perm: KCNJ11/Kir6.2 (activating/dominant)Trans/Perm: ABCC8/SUR1 (activating/dominant)Permanent: GATA6, GLIS3, MNX1, NEUROD1, NEUROG3, NKX2.2, PAX6, PDX1 / IPF1, PTF1, RFX6 (recessive)Permanent: GCK (recessive)Permanent: EIF2AK3/PERK (recessive)Permanent: INS (dominant)Autoimmune: FoxP3 (X-linked recessive)
Syndromic
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Neonatal Diabetes
Aguilar-Bryan, L. et al. Endocr Rev 2008;29:265-291
Mitochondrial Diabetes• Maternally inherited• Non-obese• Insulin deficiency• Associated with deafness and other neural defects• Caused by mutations in the mitochondrial genome
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Severe insulin Resistance
INSR (Insulin signaling)AKT2 (Insulin signaling)LMNA (Lipodystrophy)LMNB2 (Lipodystrophy)AGPAT2 (Lipodystrophy)BSCL2 (Lipodystrophy)PPARG (Lipodystrophy)
Syndromic Diabetes• Chromosomal defects: Down's,
Klinefelter's, and Turner's syndromes.• Neuromuscular syndromes: Friedreich's
ataxia, Huntington's chorea, Myotonic dystrophy, porphyria, others.
• Obesity syndromes: Laurence-Moon-Biedl, Bardet-Biedl and Preder-Willi syndromes, others.
• Wolfram's syndrome.• Thiamine Responsive Megloblastic Anemia. • Polyautommune syndromes: APS1, IPEX.
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Clinical Approach to Genetic Forms of Diabetes
• Why perform genetic tests?• Identifies family members at risk. • Provides information regarding natural
history, outcomes.• Can alter management.• What test do you do?• Depends on pretest probability, costs,
insurance.
Exome Sequencing
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Prior Probability of Specific Clinical Diagnosis
Specific Gene Testing
Whole Exome/Genome
Gene Panels
Low High
Locu
s H
eter
ogen
eity
Unknown
Large and Known
Limitedand
Known
Exome Sequencing• Originally a research tool.• Now a CLIA approved test. • Available through UCSF Diabetes and
Clinical Genetics (UCSF/UCLA).• Requires input from an experienced
geneticist.• Cannot identify with certainty all variants.• Effective when gene specific tests not
available or negative.
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Onset Neonatal
Patients with Monogenic Diabetes
TNDM6q24KATP genes
PNDMSyndromic Gene specificNonsyndromic KATP genes INS, GCK
Later
Inheritance
MaternalMitochondrial sequence
Autosomal Recessive
Autosomal Dominant
SyndromicGene specific
MODYSyndromic Gene specific HNF1B, CELNonsyndromic
EuropeansMild? = GCKSevere? = HNF1A
Non-Europeans Gene panel, ExomeNegative?
AutoimmuneAutoimmune genes
Ins ResistantResistance genes
Exome
German Lab SupportHillblom Islet Genesis Network
(Larry L. Hillblom Foundation)Nora Eccles Treadwell FoundationHelmsley Trust
Bruce BradenJuvenile Diabetes Research FoundationAmerican Diabetes Association
NIH/NIDDK, UCSF DRC
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References
• Bamshad, M.J., Ng, S.B., Bigham, A.W., Tabor, H.K., Emond, M.J., Nickerson, D.A., and Shendure, J. (2011). Exome sequencing as a tool for mendelian disease gene discovery. Nat Rev Genet 12, 745-755.• Doria, A., Patti, M.E., and Kahn, C.R. (2008). The emerging genetic architecture of type 2 diabetes. Cell Metab 8, 186-200.• Florez, J.C. (2008). Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51, 1100-1110.• Greeley, S. A. W., Naylor, R. N., Philipson, L. H., & Bell, G. I. (2011). Neonatal Diabetes: An Expanding List of Genes Allows for Improved Diagnosis and Treatment. Current Diabetes Reports, 11(6), 519–532. doi:10.1007/s11892-011-0234-7.• McCarthy, M.I., and Zeggini, E. (2009). Genome-wide association studies in type 2 diabetes. Curr Diab Rep 9, 164-171.
References
• Mehers, K.L., and Gillespie, K.M. (2008). The genetic basis for type 1 diabetes. Br Med Bull 88, 115-129.• Roach, J.C., Glusman, G., Smit, A.F., Huff, C.D., Hubley, R., Shannon, P.T., Rowen, L., Pant, K.P., Goodman, N., Bamshad, M., Shendure, J., Drmanac, R., Jorde, L.B., Hood, L., and Galas, D.J. Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing. Science.• Schwitzgebel, V.M. (2014). Many faces of monogenic diabetes. Journal of Diabetes Investigation 5, 121-133. Dickson, S.P., Wang, K., Krantz, I., Hakonarson, H., and Goldstein, D.B. Rare variants create synthetic genome-wide associations. PLoS Biol 8, e1000294.• Vaxillaire, M., and Froguel, P. (2008). Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev 29, 254-264.