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Pathogenic Alleles, Clan Genomics and the Complex Architecture of Human Disease

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Pathogenic Alleles, Clan Genomics and the Complex Architecture of Human Disease Pathogenic alleles, clan genomics and the complex architecture of human disease “High-throughput Sequencing – Applications and Analyses Oslo University 200th, NORWAY October 28, 2011 James R. Lupski, M.D., Ph.D., D.Sc. Department of Molecular & Human Genetics & Department of Pediatrics Baylor College of Medicine & Texas Children’s Hospital Houston, TX http://www.bcm.edu/geneticlabs/ Disclosure J.R.L. is a consultant for: NO affiliation with: Athena Diagnostics Life Technologies, Inc NOR 23andMe Applied BioSysytems, Inc Ion Torrent Systems Inc. Co-Inventor on Diagnostic Patents: UNITED STATES: 5,294,533 (issued 03/15/94); 5,306,616 (issued 04/26/94); 5,523,217 (issued 06/04/96); 5,599,920 (issued 02/04/97); 5,667,968 (issued 09/16/97);5,780,223 (issued 07/14/98); 6,132,954 (issued 10/19/00); 6,713,300 (issued 03/30/04); 7,141,420 (issued 11/28/06); 7,189,511 (issued 03/13/07); 7,192,579 (issued 03/20/07); 7,273,698 (issued 09/25/07). EUROPEAN: 0424473 (issued 05/08/96), 0610396 (issued 01/17/01), 0989805 (issued 01/11/06). The Medical Genetics Laboratories (MGL) of the Dept of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular diagnostic testing. MGL, http://www.bcm.edu/geneticlabs/ A story about Charcot-Marie-Tooth disease CMT: clinical & genetic aspects The CMT1A duplication - a paradigm for CNV mutation & mechanisms for CNV formation CMT mutational load - gene load? locus load? or genomic load? - SNP + CNV Personal genome sequencing: CMT Genetic contributions to inherited and apparently acquired neurologic dz CMT: clinical & genetic aspects The CMT1A duplication - a paradigm for CNV mutation & mechanisms for CNV formation CMT mutational load - gene load? locus load? or genomic load? - SNP + CNV Personal genome sequencing: CMT 1886 in Paris & Cambridge,UK Hereditary Neuropathies CMT research – the first century (105 years!). RLS CLINICAL DESCRIPTIONS MPZ 1q22 Dominant EGR2 10q21 16p13 CMT2 CMT1 LITAF/SIMPLE Primary Myelinopathy The next two decades 36 genes identified, 7 loci mapped loci 7 identified, genes 36 decades twonext The PMP22 17p12 SOX10 22q13 SH3TC2 5q32 FIG4 6q21 8q21 Recessive GENETIC MAPPING, GENETICMAPPING, GENE IDENTIFICATION GDAP1 NDRG1 8q24 HK1 10q22 SBF2 11p15 MTMR2 11q22 FGD4 12p11 Phenotype CMT CTDP1 18q23 PRX 19q13 X GJB1/Cx32 Xq13 - PRPS1 Xq21 linked Unknown Xp22 Unknown Xq24-q26 NCS/EMG Unknown Xq26-q28 Intermediate Dominant YARS 1p35 Unknown 3q13 ARHGEF10 8p23 Unknown 10q24-q25 Axonopathy Primary DNM2 19p13 LMNA 1q21 Unknown 8q21.3 Recessive LRSAM1 9q33-q34 SLC12A6 15q13 GAN 16q24 MED25 19q13 MFN2, KIF1B 1p36 RAB7 3q21 7p14 Dominant Dec 2011 Dec GARS HSPB1 7q11 NEFL 8p21 Unknown 12q12 HSPB8, TRPV4 12q24 DYNC1H1 14q32 AARS 16q22 KARS 16q23 Summary of P0 Mutations Charcot-Marie-Tooth Dejerine-Sottas Congenital Charcot-Marie-Tooth Roussy-Levy Disease Type 1 Syndrome Hypomyelination Disease Type 2 syndrome 2 Nonsense mutation 31. Ser(63)Cys 5* 31 Frameshift mutation 32. Gln(84)His, Pro(85)Leu, 45 Amino acid deletion Tyr(86)Phe, Ile(87)del 46 3 Missense 4 Insertion 33. Arg(98)Cys 6 44 aa Amino acid 34. Ile(114)Thr, 21, 22, 37 Asn(116)His, 7 18,36 8 S 34 Asp(128)Asn S 35. Thr(124)del, 32 35 50 42 19,20 16 Phe(125)del 17 23 1. Ile(30)Met 16. Asn(122)Ser 9 47 36. Lys(130)Arg 2. Thr(34)Ile 17. Thr(124)Met 2aa 48 37. Ile(135)Thr 33 41 3. Ser(63)del 18. Lys(130)Arg 15 38. Val(169)fs 10 14# * 49 4. Ser(63)Phe 19. Asp(134)Glu 39. Leu(174)fs 11,12,13 *hmz 24 5. Phe(64)del 20. Asp(134)Asn 40. Ala(221)fs 6. Ser(78)Leu 21. Ile(135)Thr 41. Asp(118)ins2aa 25 26 7. His(81)Arg 22. Ile(135)Leu 42. Thr(124)Lys 38 8. Tyr(82)Cys 23. Gly(137)Ser 43. Gln(215)Stop 39 9. Asp(90)Glu 24. Tyr(154)Stop 44.Ser(44)Phe 43 40 10. Lys(96)Glu 25. Gly(163)Arg 45. Asp(61)Gly 27 11. Arg(98)His 26. Gly(167)Arg 46. Asp(75)Val 28 12. Arg(98)Ser 27. Tyr(181)Stop 47. Tyr(119)Cys 30# 13. Arg(98)Pro 28.Leu(184)fs 48. Gln(141)Stop # 29 14. Trp(101)Cys 29. Lys(204)fs 49. Tyr(145)Ser *hmz # 15. Gly(103)fs 30. Val(232)fs 50. Asn(131)Lys Summary of P0 Mutations Charcot-Marie-Tooth Dejerine-Sottas Congenital Charcot-Marie-Tooth Roussy-Levy Disease Type 1 Syndrome Hypomyelination Disease Type 2 syndrome 2 Nonsense mutation 31. Ser(63)Cys 5* 31 Frameshift mutation 32. Gln(84)His, Pro(85)Leu, 45 Amino acid deletion Tyr(86)Phe, Ile(87)del 46 3 Missense 4 Insertion 33. Arg(98)Cys 6 44 aa Amino acid 34. Ile(114)Thr, 21, 22, 37 Asn(116)His, 7 18,36 8 S 34 Asp(128)Asn S 35. Thr(124)del, 32 35 50 42 19,20 16 Phe(125)del 17 23 1. Ile(30)Met 9 47 16. Asn(122)Ser 36. Lys(130)Arg 2. Thr(34)Ile 17. Thr(124)Met 2aa 48 37. Ile(135)Thr 33 41 3. Ser(63)del 15 18. Lys(130)Arg 38. Val(169)fs 10 14# * 49 4. Ser(63)Phe 19. Asp(134)Glu 39. Leu(174)fs 11,12,13 *hmz 24 5. Phe(64)del 20. Asp(134)Asn 40. Ala(221)fs 6. Ser(78)Leu 21. Ile(135)Thr 41. Asp(118)ins2aa 25 26 7. His(81)Arg 22. Ile(135)Leu 42. Thr(124)Lys 38 8. Tyr(82)Cys 23. Gly(137)Ser 43. Gln(215)Stop 39 9. Asp(90)Glu 24. Tyr(154)Stop 44.Ser(44)Phe 43 40 10. Lys(96)Glu 25. Gly(163)Arg 45. Asp(61)Gly 27 11. Arg(98)His 26. Gly(167)Arg 46. Asp(75)Val 28 12. Arg(98)Ser 27. Tyr(181)Stop 47. Tyr(119)Cys 30# 13. Arg(98)Pro 28.Leu(184)fs 48. Gln(141)Stop # 29 14. Trp(101)Cys 29. Lys(204)fs 49. Tyr(145)Ser *hmz 15. Gly(103)fs 30. Val(232)fs# 50. Asn(131)Lys Molecular architecture of the myelinated axon FIG4 FGD4 Niemann, Berger and Suter, NeuroMolecular Medicine, 2006;8:217-24 (updated) What have we learnt? One can perturb the neuron/nerve in a multitude of ways = CMT Genetic contributions to inherited and apparently acquired neurologic dz CMT: clinical & genetic aspects The CMT1A duplication - a paradigm for CNV mutation & mechanisms for CNV formation CMT mutational load - gene load? locus load? or genomic load? - SNP + CNV Personal genome sequencing: CMT & DRD The CMT1A duplication – a CNV paradigm Raeymakers, Timmerman, et al. (1991) Neuromuscular Disorders 1 :93-97 Lupski, et al. (1991) Cell 66 :219-232; Lupski, et al (1992) Nat Genet 1 :29-33 [duplication, gene dosage] ; Pentao, Liu, et al (1992) Nat Genet 2 :292-300 [NAHR] Proximal Distal CMT1A-REP CMT1A-REP ~ 70% of all CMT1 pts A B C D 76-90% of sporadic CMT1 PMP22 [de novo mutation] NORMAL: PMP22 = 2n A‟ B‟ C‟ D‟ CMT1A: PMP22 = 3n HNPP: PMP22 = 1n A B C B‟ C‟ D‟ A‟ D CNV dzs: SCZ Autism JCT JCT Obesity CMT1A DUPLICATION HNPP DELETION STR RFLP independent molecular methods reveal evidence for CMT1A duplication fiber-FISH Rautenstrauss (1997) J Periph Nerv Sys 3:1-4 What have we learned? CNV associated with genomic disorders highlight: i) Disease allele transmission; FISH PFGE dup CNV = triallelic Patel and Lupski (1994) TIG 10:128-133 ii) Gene dosage role in clinical traits Contrasting features of CMT1A and HNPP CMT1A HNPP Clinical Symmetric, slowly progressive Asymmetric, episodic Antecedent None Motor nerve compression Mild delay in achieving motor milestones None Potential Early Signs Idiopathic toe walking of childhood Absent deep tendon reflexes Distal muscle weakness and atrophy Pressure palsies Presentation Dropped foot abnormal gait Focal neuropathy Foot deformity (pes cavus, pes planus) Carpal tunnel syndrome Electrophysiologic Slow NCV Conduction block Neuropathology Onion bulb Tomacula Molecular Duplication Deletion HMZ dup gives severe disease: gene dosage! Lupski et al. 1991 Cell 66:219-232 PHENOTYPIC VARIABILITY Charcot-Marie-Tooth type 1 Roussy-Levy syndrome Dejerine-Sottas syndrome CMT1A (hmz > htz) duplication HMSN with calf hypertrophy Scapuloperoneal atrophy (Davidenkow syndrome) Ann. Neurol. (1996) 39:180-186 . 24/51 patients with multifocal neuropathy have HNPP deletion . 7/19 (37%) index cases had no affected relatives . Peripheral nerve lesion related to pressure in only 62% of cases Multifocal neuropathy genetic? PMP22 CNV detected by abnormal MLPA for CMT1A duplication dup/del Year test nml dup del 2007 4261 3472 549 194 •MLPA unusual in 7 samples •Frequency of detecting dup or del = (549+194)/4261 = 17.5% •Frequency of unusual MLPA = 7/(549+194) = 0.8% •Estimated NAHR at CMT1A/HNPP locus = 99.2% • del/dup = 194/549 = ~.35 (NOT 2:1); ~80% HNPP undiagnosed! Zhang et al (2009) Nature Genetics 41:849-853 CNVs involving the coding or upstream regions of PMP22 from patients with CMT1A or HNPP Zhang, et al.(2010) Am J Hum Genet 86:892-903 Rare CNVs as a Cause for Missing Heritability > 99% CMT1A pts Exonic deletions of PMP22 A10 Dist_Ref GTTGGGATTACAGG A10 GTTGGGATTCCAGG (17 kb) Prox_Ref CTATAGATTCCAGG Dist_Ref GTGTCACCAAAT A11 A11 GTGTCACACCTG (7 kb) Prox_Ref CTTAGACACCTG A15 (9 kb) A21 Dist_Ref CCTGCTCTGCTTT A21 CCTGCTCCGCCCG (12 kb) Prox_Ref GCCCGACCGCCCG SPR2 Dist_Ref ATTTTTAAATCATTT SPR2 ATTTTTCATTGCTGA (17 kb) Prox_Ref GTTGGGGGCTGCTGA A29 Dist_Ref TACACGTCAGGTCC A29 TACACGTCCCCAGT (13 kb) Prox_Ref TAGGGATCCCCAGT A23 Dist_Ref CCATGCAAACCCA A23 CCATGCAGACCCA (5 kb) Prox_Ref CTGGGAAGACCCA 5 4 32 PMP22 exons FoSTeS caused complex deletion of PMP22 exon 4 CMT1 57 m/s 55 m/s median NCV 11 m/s 7 m/s A B MarkerPat Mat Pt1 Sib Pt2 Crtl ~1.2 kb standard PCR; primers A ~10 kb ~1.7 kb Mosaic complex rearrangement in mother suggests mitotic event consistent with the MMBIR/FoSTeS model long-range PCR; primers B Zhang et al.
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