normal size LV,! dilated LV with! normal contractility! contractile dysfunction! • Phenotype: 20-35% of IDC probands have familial dilated cardiomyopathy (FDC) with clinical screening of family members (echo/ ECG)! • Genotype: rare variants found in >30 genes! • Only 30-35% of FDC genetic cause known! • Rare coding variants! • Mostly autosomal dominant! • Marked allelic and locus heterogeneity! • Adult onset with reduced penetrance! • Mutation frequency low to very low in any gene! • Only 30-35% of FDC genetic cause known! Crispell, et al, JACC, 1999; 34:837-47! Maximal lod score of left hand peak increased by almost one lod unit when decendants of the FDC-1 proband set to "unknown# status for linkage analysis! het SNPs hom SNPs present in all number present in all number F1-Core Analysis A: F1 core 3 genes F1 core 3 genes Non-synon, splice variants, not in dbSNP/1000 genomes 97 62 9 8 above, not in 8 hapmap individuals 51 36 5 4 above, not in Zuchner 454 data 39 30 2 2 above, not in multiple pedigrees (10 or more) 14 13 1 1 above, polyphen probably / possibly damaging 0 0 0 0 above, polyphen probably damaging 0 0 0 0 het SNPs hom SNPs number present in all present in all number genes F1-Core Analysis B F1-B F1-B genes Non-synon, splice variants, not in dbSNP/1000 genomes 316 242 22 18 above, not in 8 hapmap individuals 208 182 14 11 above, not in Zuchner 454 data 181 162 9 7 above, not in multiple pedigrees (10 or more) 149 143 6 6 above, polyphen probably / possibly damaging 11 11 1 1 above, polyphen probably damaging 2 2 1 1 het SNPs hom SNPs number present in all present in all number genes F1-A and F1-B F1-A, F1B F1A, F1-B genes Non-synon, splice variants, not in dbSNP/1000 genomes 70 37 8 7 above, not in 8 hapmap individuals 34 21 4 3 above, not in Zuchner 454 data 24 17 1 1 above, not in multiple pedigrees (10 or more) 1 1 0 0 above, polyphen probably / possibly damaging 0 0 0 0 above, polyphen probably damaging 0 0 0 0 Hapmap from Ng et al, Nature 2009;461:272-76; Zuchner 454 data from Hedges et al, Plos ONE 2009;4:e8232! *Cooper et al Nature Methods 2010;7:250-251! • Await remainder of exome sequence data! • Confirm high interest rare variants by resequencing in proband and selected affected subjects ! • Sequence full pedigree if rare variant confirmed! • Rule out other promising candidates! • Search for allelic variants of vetted and putative disease- causing gene in our cohort of >450 FDC/IDC probands! • Functional studies! Exome sequencing provides a remarkably powerful novel discovery approach for autosomal dominant rare variant disease! Our heartfelt thanks to: ! • the UW Genome Sciences group for selecting these pedigrees for study!! • the NHLBI/NHGRI for exome center support ! • the NHLBI for supporting our FDC project studies (R01 HL58626)! Research Teams" Supported by NHLBI: RO1 HL 58626 !Research website www.fdc.to! June #09! F1-A core 3 - 13 genes F1-B - 143 genes F1-AB intersect ZWILCH 15_64619520 ABCC12 CNTROB KIF21B OR2T34 PTCD3 TMIGD2 COLQ ARHGEF5 7_143691219 ADAMTS12 COLQ KRT33A OR2T5 RAB11FIP2 TNC OLFML1 11_7463758 ADAMTSL4 CPS1 KRT6B OR2T8 RAD54B TPSAB1 VCX3A X_6461989 AGL DBT KRT71 OR4A16 RANBP2 TRAK1 No polyphen MAGEC1 X_140821613 AGRN DHX33 LOC284801 OR52J3 RNF146 TRIM47 predictions COLQ 3_15482929 AHCTF1 DMRT1 LOH11CR2A OR6C68 RPS6KC1 TSSC4 C20orf195 20_61658251 AMZ2 ELL LRP2 OR7D2 RSPH1 TTC26 available for UGT2B11 4_70100965 APIP ELL2 LRP4 OSMR S100A3 TTC3 COLQ! ASTN2 9_118531098 ATE1 ERBB4 LYL1 PABPC1 SAMD9 TYRO3 TGIF1 18_3442030 ATP5B F13A1 MAGEC1 PCDHB15 SCLT1 UNC45B FSIP1 15_37697619 AVPR1B FADS3 MARCH7 PDXDC1 SFRS12 VCX High genomic IL17RC 3_9945081 AZI1 FAM115C,FAM139AMGC34761 PHF17 SHISA2 VIL1 evolutionary DISP2 15_38447163 BUB1 FCRL3 MIF4GD PKD1 SLC25A22 VNN2 rate profiling C11orf16 FLJ10769 MRPS28 PLA2G4D SLC25A31 XAB2 C2CD3 FN1 MUPCDH PLEKHN1 SPAG17 XIRP1 (GERP) score* C2orf57 GBP3 MYH1,LOC100128560PMS2 SPATA16 XKR9 of 5.69 at that C9orf79 GBX2,LOC100128572NDUFAB1 POLR2J2 SPINT1 ZBTB20 C9orf93 GLOD4 NEO1 PPIL1 SULT2B1 ZFP106 position! CADPS GMIP NFE2L1 PRAMEF1 TAF1A ZNF423 CBS HLA-DPA1 NOXO1 PRAMEF4 TCFL5 ZNF434 CCDC74B IL17RC NPHS1 PRIC285 TET2 ZNF608 CD300LG IMP5,LOC100128977NT5C3 PRLR TJP3 ZNF80 CENPF JARID1B OR11H1 PRSSL1 TMC6 ZNF804B CGNL1 KIAA1524 OR2L13,OR2L3PSG4 TMC8 *Cooper et al Nature Methods 2010;7:250-251!.