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A Method for Rapid, Targeted CNV Genotyping Identifies Rare ...

  1. 1. A Method for Rapid, Targeted CNV Genotyping Identifies Rare Variants Associated with Neurological Disease Gregory Cooper, Ph.D. Department of Genome Sciences, University of Washington
  2. 2. Genomic Structural Variation Human Genetic Variation Frequency 1 bp 1 chr Size
  3. 3. Genomic Structural Variation Human Genetic Variation SNPs Frequency 1 bp 1 chr Size
  4. 4. Genomic Structural Variation Human Genetic Variation SNPs Frequency cytogenetic 1 bp 1 chr Size
  5. 5. Genomic Structural Variation Human Genetic Variation SNPs Frequency structural variation cytogenetic 1 bp 1 chr Size
  6. 6. Genomic Structural Variation Human Genetic Variation deletions SNPs insertions Frequency structural variation cytogenetic 1 bp 1 chr Size
  7. 7. Genomic Structural Variation Human Genetic Variation deletions SNPs insertions duplications Frequency structural variation cytogenetic 1 bp 1 chr Size
  8. 8. Genomic Structural Variation Human Genetic Copy-Number Variants Variation deletions SNPs insertions duplications Frequency structural variation cytogenetic 1 bp 1 chr Size
  9. 9. Genomic Structural Variation Human Genetic Copy-Number Variants Variation deletions SNPs insertions duplications Frequency structural variation • Gene-rich, e.g. immune response, drug metabolism • Abundant: majority of human cytogenetic heterozygosity 1 bp 1 chr • Technological challenges have Size impeded large-scale analyses
  10. 10. SNP-based Deletion Discovery
  11. 11. SNP-based Deletion Discovery A B BA BA B B 1234
  12. 12. SNP-based Deletion Discovery A B BA BA B B 1234 1 CopyNum=2 ‘LogR’ 0 -1 1234
  13. 13. SNP-based Deletion Discovery A B BA BA B B 1234 1 CopyNum=2 ‘LogR’ 0 -1 1234 ‘B-Allele Freq’ 1 BB 0.5 AB 0 1234
  14. 14. SNP-based Deletion Discovery A B BA A B BA BA B B 1234 1234 1 1 CopyNum=2 CopyNum=1 ‘LogR’ LogR 0 0 -1 -1 1234 1234 ‘B-Allele Freq’ B-Allele Freq 1 BB 1 B- 0.5 0.5 AB 0 0 A- 1234 1234
  15. 15. Illumina 1M Deletion Discovery 1 LogR and B-Allele Frequency 1.0 ● ●● ●●●● ● ●● ●● ● ● ● ●● ● ●● ● ● ● ● ● ● ●● ●● ● ● ●● ●● ● ● ● 0.5 ● ● ● ● ● ● ● 0.5 ● ● ● ● ● ● ● ● ● ● ● ● LogR and B−Allele Freq 0 ● 0.0 ● ● ● ● ● ● ● ● ● ●● ●● ●● ● -0.5 −0.5 fosmid-inferred breakpoints -1 −1.0 ~55 kbp 46700000 Human chromosome 3 position 46740000 46770000 46810000 46850000 4689000 chr3 coordinates
  16. 16. Illumina 1M Deletion Discovery 1 LogR and B-Allele Frequency 1.0 ● ●● ●●●● ● ●● ●● ● ● ● ●● ● ●● ● ● ● ● ● ● ●● ●● ● ● ●● ●● ● ● ● 0.5 ● ● ● ● ● ● ● 0.5 ● ● ● ● ● ● ● ● ● ● ● ● LogR and B−Allele Freq 0 ● 0.0 ● ● ● ● ● ● ● ● ● ●● ●● ●● ● -0.5 −0.5 fosmid-inferred breakpoints -1 −1.0 ~55 kbp 46700000 Human chromosome 3 position 46740000 46770000 46810000 46850000 4689000 chr3 coordinates
  17. 17. SNP-based Duplication Discovery A B BA A B BA A B BA BA B B BA B B 1234 1234 1 1 CopyNum=2 LogR LogR 0 0 CopyNum=3 -1 -1 1234 1234 BBB B-Allele Freq B-Allele Freq 1 BB 1 ABB 0.5 0.5 AB AAB 0 0 1234 1234
  18. 18. Illumina 1M Duplication Discovery 1 LogR and B-Allele Frequency 1.0 ●● ● ●● ● ● ● ● ●●● ● ● ● ● ●● ● ●●● ● ● ●●●● ● ●●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●● ● ● ● ● ● ● 0.5 ● ● ● ● ● ● ● ●● 0.5 ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● LogR and B−Allele Freq ● ● ● ●● ● ● ● ● ● ● ● ● ● ● 0 ● 0.0 ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ●●● ● ● ●● ● ● ● ● ●●● ● ●● ● -0.5 −0.5 -1 −1.0 ~90 kbp 75630000 75690000 Human chromosome 2 position 75750000 75810000 75860000 75920000 chr2 coordinates
  19. 19. Illumina 1M Duplication Discovery 1 LogR and B-Allele Frequency 1.0 ●● ● ●● ● ● ● ● ●●● ● ● ● ● ●● ● ●●● ● ● ●●●● ● ●●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●● ● ● ● ● ● ● 0.5 ● ● ● ● ● ● ● ●● 0.5 ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● LogR and B−Allele Freq ● ● ● ●● ● ● ● ● ● ● ● ● ● ● 0 ● 0.0 ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ●●● ● ● ●● ● ● ● ● ●●● ● ●● ● -0.5 −0.5 fosmids independently inferred to harbor -1 −1.0 duplication ~90 kbp 75630000 75690000 Human chromosome 2 position 75750000 75810000 75860000 75920000 chr2 coordinates
  20. 20. Discovering CNVs in Large Cohorts • ~1,000 individuals from the PARC project (Illumina 317k SNP arrays) • Caucasian samples from a statin pharmacogenetics study • ~1,000 samples from the Human Genome Diversity Panel (Illumina 650Y chips; Li, Absher, et al Science 2008): • samples collected in diverse regions of the world • ~800 neurological disease controls (Illumina 550K chips; Andy Singleton; Walsh et al, Science 2008) • samples screened for symptoms of psychiatric disease • n = 2,493 samples after QC (600 blood DNA)
  21. 21. Large CNV Overview Study Platform # Samples CNVs Calls/Sample PARC HH317K 936 (991) 2,664 2.85 Neurological Disease HH550K 671 (790) 4,641 6.92 Controls HGDP HH650Y 886 (941) 6,538 7.38 2,493 Total 13,843 5.56 (2,722)
  22. 22. R: 1254x827 Many Individuals Carry Large Events 100% 1.00 Singleton -Coriell Controls (550K, cells) Coriell Singleton -NINDS Controls (550K, cells) NINDS PARC (’CAP’) (317K, cells) cap 0.50 50% PARC (’PRINCE’) (317K, blood) prince HGDP (650Y, cells) stanford Combined Combined 0.20 20% Fraction of Individuals tenkb.indcounts/sum(study.indcounts) 10% 0.10 5% 0.05 0.02 2% 1% 0.01 0 0e+00 100 200 2e+05 300 400 4e+05 500 600 6e+05 700 800 8e+05 900 1000 1e+06 Minimum Size (kb) size_indeces
  23. 23. Collectively Frequent But Individually Rare Itsara et al. Figure 5. 2e+07 1e+07 10000 Homozygous Deletions Deletions 5e+06 5000 Duplications # Genes: 2e+06 2000 0 10 50 5e+05 1e+06 1000 2e+05 CNV Size (kb) 500 200 1e+05 100 5e+04 50 1 1 2 2 3 3 4-5 4 6-10 5 10-25 6 >25 7 Number of Individuals plot.index + jitter[AssignedState + 1]
  24. 24. Genomic CNV ‘HotSpots’ Duplication/Deletion HotSpot >95% identical • Non-Allelic Homologous Recombination (NAHR) between duplicated sequences results in novel CNVs • Thousands of potential hotspots in the reference assembly (1 kb to Mbps in size) • de novo hotspot mutations have been implicated as causative for a number of diseases
  25. 25. CNVs Enriched Near Segmental Duplications LogR and B-Allele Frequency 1.0 ●● ● ● ● ●● ● ● ●●●● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ●●● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● 0.5 ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ●● ● ●● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● LogR and B−Allele Freq ●●● ● ● ● 0.0 ● ● ● ● ●●● ● ● ●● ● ●● ● ●● ● ● ●● ●● ●● ●● ● ● ● ●● ● ● ● ●● ●● ● ● ● ● ●● ●●● ●●● ● ● ● ●● ● ● −0.5 −1.0 62810000 63420000 64020000 64630000 65240000 65840000 chr7 chr7 coordinates −− stanford.un.hmm.HGDP00382
  26. 26. CNVs Enriched Near Segmental Duplications LogR and B-Allele Frequency 1.0 ●● ● ●●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●●● ●● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● 0.5 ●● ● ● ● ● ● ● ● ● ● ●● ●● ●● ● ● ● ● ● ●● ● ● ● ●● ●●● ● ●● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● LogR and B−Allele Freq ● 0.0 ● ● ● ●● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ●● ●●● ● ●● ●● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ●● ●● ●● ●● ● ●● ● ● ● ● −0.5 −1.0 62810000 63420000 64020000 64630000 65240000 65840000 chr7 chr7 coordinates −− stanford.un.hmm.HGDP00876
  27. 27. 1.0 CNVs Enriched Near Segmental Duplications 1.0 ●● ● ● ● ●● ● ● ●●●● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ●●● ● ● ● ● ●● ● ●●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●●● ●● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● 0.5 ● ●● ● ●● ● ● ● ● 0.5 ● ● ● ● ● ●● ● ●● ●● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ●● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ●●● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ●● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● LogR and B−Allele Freq LogR and B−Allele Freq ●●● ● ● ● ● 0.0 0.0 ● ● ● ● ● ●●● ● ● ●● ● ●● ● ●● ● ● ●● ●● ●● ●● ● ● ● ●● ● ● ● ●● ●● ● ● ● ● ●● ●●● ●●● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ●● ●●● ● ●● ●● ● ● ● ● ●● ●● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ●● ●● ● ● ● ● ●● ●● ●● ●● ● ●● ● ● ● ● −0.5 −0.5 −1.0 −1.0 62810000 63420000 64020000 64630000 65240000 65840000 62810000 63420000 64020000 64630000 65240000 65840000 chr7 coordinates −− stanford.un.hmm.HGDP00876 chr7 coordinates −− stanford.un.hmm.HGDP00382 25X enrichment for CNVs between homologous duplications in the reference assembly
  28. 28. Hotspots Increase CNV Frequencies Duplications ~1% increase CNV allele frequency
  29. 29. Large ‘HotSpot’ Duplication 1 1.0 LogR and B-Allele Frequency ●●● ● ● ● ●● ●● ●● ● ●● ● ●● ● ● ● ●● ●● ● ● ● ● ●● ●●● ● ● ● ● ● ● ●●● ● ● ● ● ●●● ● ●●●●●●● ● ●● ● ● ● ●●● ● ● ● ●● ● ● ●●●●● ● ●● ● ● ● ● ●● ●● ● ● ● ● ●● ● ● ● ● ● BP4 ●● ● ● BP5 ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●● ● ● ●●●● ● ● ● ●● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● 0.5 ● ● ● ● ● ● ● ●● ● ● ●● ● ●● ● 0.5 ● ●● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● LogR and B−Allele Freq ● ● ● ●● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ●● ● 0 ● 0.0 ●● ● ●●● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ●●● ● ● ●● ● ● ● ● ●● ● ● ● ●● ● ●● ● ● ● ●● ● ● ●● ●● ● ●● ● ● ●●● ●●● ●● ● ● ● ● ● ●●● ● ● ●●● ●● -0.5 −0.5 1.8 Mbp -1 −1.0 27720000 chr15q13, near Prader-Willi 28470000 29230000 29990000 30740000 31500000
  30. 30. Large ‘HotSpot’ Duplication 1 1.0 LogR and B-Allele Frequency ●●● ● ● ● ●● ●● ●● ● ●● ● ●● ● ● ● ●● ●● ● ● ● ● ●● ●●● ● ● ● ● ● ● ●●● ● ● ● ● ●●● ● ●●●●●●● ● ●● ● ● ● ●●● ● ● ● ●● ● ● ●●●●● ● ●● ● ● ● ● ●● ●● ● ● ● ● ●● ● ● ● ● ● BP4 ●● ● ● BP5 ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●● ● ● ●●●● ● ● ● ●● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● 0.5 ● ● ● ● ● ● ● ●● ● ● ●● ● ●● ● 0.5 ● ●● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● LogR and B−Allele Freq ● ● ● ●● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ●● ● 0 ● 0.0 ●● ● ●●● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ●●● ● ● ●● ● ● ● ● ●● ● ● ● ●● ● ●● ● ● ● ●● ● ● ●● ●● ● ●● ● ● ●●● ●●● ●● ● ● ● ● ● ●●● ● ● ●●● ●● -0.5 −0.5 1.8 Mbp -1 Reciprocal Deletion Associates with ID (Sharp et −1.0 al. 2008) and Epilepsy (Helbig et al. 2009) 27720000 chr15q13, near Prader-Willi 28470000 29230000 29990000 30740000 31500000
  31. 31. Neurological Disease Meta-Analysis • Combined our ~2,500 samples with published CNV calls from ~3,000 controls analyzed using Affymetrix arrays (ISC Nature 2008) • Combined genome-wide CNV annotations from 9 disease studies: • schizophrenia: ~3,500 individuals • autism: ~2,500 individuals • intellectual disability: ~500 individuals • mixture of Affy, Illumina, and CGH • only analyzed CNVs > 500 kb
  32. 32. Neurological Disease Meta-Analysis Disease Disease Controls 1 Mb Controls 1 Mb Deletions Duplications
  33. 33. Neurological Disease Meta-Analysis Disease Disease Controls 1 Mb Controls 1 Mb 22q11-12 (VCFS) Prader Willi,15q13 Deletions Duplications
  34. 34. Neurological Disease Meta-Analysis Disease Disease Controls 1 Mb Controls 1 Mb 16p12 ? 15q25 ? Deletions Duplications
  35. 35. Neurological Disease CNVs Disease Control Chr Start Stop Type Note NAHR? Diseases CNVs CNVs chr22 17,014,900 19,993,127 loss VCFS yes 31 0 A,S,ID chr15 27,015,263 30,650,000 loss 15q13 yes 19 0 S chr1 142,540,000 146,059,433 loss 1q21.1 yes 24 3 A,S,C chr15 18,376,200 30,756,771 gain PW/15q13 yes 45 13 A,S,ID,C chr1 142,800,580 146,009,436 gain 1q21.1 yes 12 3 A,S,ID,C chr16 21,693,739 22,611,363 loss 16p12 yes 5 0 A,S chr22 45,144,027 49,509,153 loss Term 22 no 4 0 A chr16 60,141,700 61,581,600 loss 16q21 no 4 0 A chr15 82,573,421 83,631,697 loss 15q25 yes 4 0 A,S chr16 80,737,839 82,208,451 gain 16q23.3 no 4 0 A,S chr16 29,474,810 30,235,818 gain 16p11.2 yes 6 1 A,S,C chr17 14,000,000 15,421,835 loss HNPP yes 6 1 A,S,C chr22 47,572,875 48,323,417 gain Term 22 no 5 1 A,S,C chr11 78,120,000 85,610,000 loss 11q14 no 3 0 S,ID chr2 184,270,000 186,892,000 gain 2q32 no 3 0 A chr9 206456 1599250 gain 9p24 no 3 0 A,S chr3 197,179,156 198,842,299 loss 3q29 yes 3 0 S chr16 29,470,951 30,252,473 loss 16p11.2 yes 8 3 A,C chr17 12,650,000 15,540,000 gain CMT1A yes 4 1 A,S,ID,C
  36. 36. Neurological Disease CNVs Disease Control Chr Start Stop Type Note NAHR? Diseases CNVs CNVs chr22 17,014,900 19,993,127 loss VCFS yes 31 0 A,S,ID chr15 27,015,263 30,650,000 loss 15q13 yes 19 0 S chr1 142,540,000 146,059,433 loss 1q21.1 yes 24 3 A,S,C chr15 18,376,200 30,756,771 gain PW/15q13 yes 45 13 A,S,ID,C chr1 142,800,580 146,009,436 gain 1q21.1 yes 12 3 A,S,ID,C chr16 21,693,739 22,611,363 loss 16p12 yes 5 0 A,S chr22 45,144,027 49,509,153 loss Term 22 no 4 0 A chr16 60,141,700 61,581,600 loss 16q21 no 4 0 A chr15 82,573,421 83,631,697 loss 15q25 yes 4 0 A,S chr16 80,737,839 82,208,451 gain 16q23.3 no 4 0 A,S chr16 29,474,810 30,235,818 gain 16p11.2 yes 6 1 A,S,C chr17 14,000,000 15,421,835 loss HNPP yes 6 1 A,S,C chr22 47,572,875 48,323,417 gain Term 22 no 5 1 A,S,C chr11 78,120,000 85,610,000 loss 11q14 no 3 0 S,ID chr2 184,270,000 186,892,000 gain 2q32 no 3 0 A chr9 206456 1599250 gain 9p24 no 3 0 A,S chr3 197,179,156 198,842,299 loss 3q29 yes 3 0 S chr16 29,470,951 30,252,473 loss 16p11.2 yes 8 3 A,C chr17 12,650,000 15,540,000 gain CMT1A yes 4 1 A,S,ID,C
  37. 37. Neurological Disease CNVs Disease Control Chr Start Stop Type Note NAHR? Diseases CNVs CNVs chr22 17,014,900 19,993,127 loss VCFS yes 31 0 A,S,ID chr15 27,015,263 30,650,000 loss 15q13 yes 19 0 S chr1 142,540,000 146,059,433 loss 1q21.1 yes 24 3 A,S,C chr15 18,376,200 30,756,771 gain PW/15q13 yes 45 13 A,S,ID,C chr1 142,800,580 146,009,436 gain 1q21.1 yes 12 3 A,S,ID,C chr16 21,693,739 22,611,363 loss 16p12 yes 5 0 A,S chr22 45,144,027 49,509,153 loss Term 22 no 4 0 A chr16 60,141,700 61,581,600 loss 16q21 no 4 0 A chr15 82,573,421 83,631,697 loss 15q25 yes 4 0 A,S chr16 80,737,839 82,208,451 gain 16q23.3 no 4 0 A,S chr16 29,474,810 30,235,818 gain 16p11.2 yes 6 1 A,S,C chr17 14,000,000 15,421,835 loss HNPP yes 6 1 A,S,C chr22 47,572,875 48,323,417 gain Term 22 no 5 1 A,S,C chr11 78,120,000 85,610,000 loss 11q14 no 3 0 S,ID chr2 184,270,000 186,892,000 gain 2q32 no 3 0 A chr9 206456 1599250 gain 9p24 no 3 0 A,S chr3 197,179,156 198,842,299 loss 3q29 yes 3 0 S chr16 29,470,951 30,252,473 loss 16p11.2 yes 8 3 A,C chr17 12,650,000 15,540,000 gain CMT1A yes 4 1 A,S,ID,C
  38. 38. Neurological Disease CNVs Disease Control Chr Start Stop Type Note NAHR? Diseases CNVs CNVs chr22 17,014,900 19,993,127 loss VCFS yes 31 0 A,S,ID chr15 27,015,263 30,650,000 loss 15q13 yes 19 0 S chr1 142,540,000 146,059,433 loss 1q21.1 yes 24 3 A,S,C chr15 18,376,200 30,756,771 gain PW/15q13 yes 45 13 A,S,ID,C chr1 142,800,580 146,009,436 gain 1q21.1 yes 12 3 A,S,ID,C chr16 21,693,739 22,611,363 loss 16p12 yes 5 0 A,S chr22 45,144,027 49,509,153 loss Term 22 no 4 0 A •3q29 independently reported as an ID syndrome chr16 60,141,700 61,581,600 loss 16q21 no 4 0 A •16p12 deletion present in: chr15 82,573,421 83,631,697 chr16 80,737,839 82,208,451 loss gain 15q25 16q23.3 yes no 4 4 0 0 A,S A,S • chr16 schizophrenia/ID affected family (from Mary-Claire 1 a 29,474,810 30,235,818 gain 16p11.2 yes 6 King) A,S,C • chr17 schizophrenic and 2 control samples (from 6 3 14,000,000 15,421,835 gain chr22 47,572,875 48,323,417 loss HNPP Term 22 yes no Jonathan Sebat) 5 1 1 A,S,C A,S,C • chr11 78,120,000 ~10,000 children with various cognitive deficits (Lisa 12 out of 85,610,000 loss 11q14 no 3 0 S,ID chr2 184,270,000 186,892,000 gain 2q32 no 3 0 A Shaffer and Signature Genomics) chr9 206456 1599250 gain 9p24 no 3 0 A,S chr3 197,179,156 198,842,299 loss 3q29 yes 3 0 S chr16 29,470,951 30,252,473 loss 16p11.2 yes 8 3 A,C chr17 12,650,000 15,540,000 gain CMT1A yes 4 1 A,S,ID,C

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