0e0f3ee62e8b58568088d9d330b1b55c ijms-25-08473.pdf f2f9f92d25e2118a3b2d206032257e14672ff6c6 ijms-25-08473.pdf 54cda2ca9f7dc6c2e979734800e69ecfacf960454500b4e470d8bc3b85d2c547 ijms-25-08473.pdf Title: Patients with Thyroid Dyshormonogenesis and DUOX2 Variants: Molecular and Clinical Description and Genotype–Phenotype Correlation Subject: Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype–phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype–phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants. Keywords: congenital hypothyroidism; CH; thyroid dyshormonogenesis; dual oxidase 2; DUOX2; phenotypic variability Author: Noelia Baz-Redón, María Antolín, María Clemente, Ariadna Campos, Eduard Mogas, Mónica Fernández-Cancio, Elisenda Zafon, Elena García-Arumí, Laura Soler, Núria González-Llorens, Cristina Aguilar-Riera, Núria Camats-Tarruella and Diego Yeste Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Sat Aug 3 06:17:45 2024 CEST ModDate: Sat Aug 3 06:23:54 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 675942 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JCYIDT+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 WLCCNX+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 RGUDEV+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 SCAGMU+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 IFHNQT+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 CIQLLF+VnURWPalladioL Type 1 Custom yes yes yes 37 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 53 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 56 0 LOEJIH+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 85 0 LOEJIJ+PalatinoLinotype TrueType WinAnsi yes yes no 88 0 LOEJIL+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 91 0 THOBMO+CMSY10 Type 1 Builtin yes yes yes 99 0 MPUDFL+PazoMath Type 1 Builtin yes yes yes 119 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-11-25 04:12:23 CET RepresentationInformation: ijms-25-08473.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-11-24 16:14:51 CET Size: 675942 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 399 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Genetic Results Destination: subsection.2.1 Item: Title: In Silico Studies Results Destination: subsection.2.2 Item: Title: Patients’ Evaluation, Biochemical Analyses, and Classification Destination: subsection.2.3 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Patients and Clinical Evaluation Destination: subsection.4.1 Item: Title: Genetics Destination: subsection.4.2 Item: Title: In Silico Studies Destination: subsection.4.3 Item: Title: References Destination: appendix.A. Info: Title: Patients with Thyroid Dyshormonogenesis and DUOX2 Variants: Molecular and Clinical Description and Genotype Phenotype Correlation Author: Noelia Baz-Redón, María Antolín, María Clemente, Ariadna Campos, Eduard Mogas, Mónica Fernández-Cancio, Elisenda Zafon, Elena García-Arumí, Laura Soler, Núria González-Llorens, Cristina Aguilar-Riera, Núria Camats-Tarruella and Diego Yeste Subject: Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants. Keywords: congenital hypothyroidism; CH; thyroid dyshormonogenesis; dual oxidase 2; DUOX2; phenotypic variability Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Sat Aug 03 06:17:45 CEST 2024 ModDate: Sat Aug 03 06:23:54 CEST 2024 ID: 0x396f6eb112d98f9d2241463cd7ee96f7, 0x396f6eb112d98f9d2241463cd7ee96f7 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: WLCCNX+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 150 FontDescriptor: FontName: WLCCNX+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: IFHNQT+URWPalladioL-BoldItal FontSubset: true FirstChar: 50 LastChar: 88 FontDescriptor: FontName: IFHNQT+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: THOBMO+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: THOBMO+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true ToUnicode: true Font: BaseFont: CIQLLF+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: CIQLLF+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: RGUDEV+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: RGUDEV+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: MPUDFL+PazoMath FontSubset: true FirstChar: 68 LastChar: 68 FontDescriptor: FontName: MPUDFL+PazoMath Flags: Symbolic FontBBox: -40, -283, 878, 946 FontFile: true ToUnicode: true Font: BaseFont: JCYIDT+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 243 FontDescriptor: FontName: JCYIDT+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: SCAGMU+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: SCAGMU+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 116, 281, 152, 290 Annotation: Subtype: Link Rect: 34, 269, 130, 278 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 125, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 149, 87 Annotation: Subtype: Link Rect: 34, 756, 180, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 137, 642, 148, 655 Annotation: Subtype: Link Rect: 528, 642, 539, 655 Annotation: Subtype: Link Rect: 548, 630, 559, 643 Annotation: Subtype: Link Rect: 142, 617, 153, 630 Annotation: Subtype: Link Rect: 277, 617, 288, 630 Annotation: Subtype: Link Rect: 389, 617, 400, 630 Annotation: Subtype: Link Rect: 469, 93, 476, 102 ActionDest: 131 Annotation: Subtype: Link Rect: 476, 93, 483, 102 ActionDest: 131 Annotation: Subtype: Link Rect: 139, 17, 278, 28 Annotation: Subtype: Link Rect: 422, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 402, 87, 421 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 208, 731, 215, 740 ActionDest: 131 Annotation: Subtype: Link Rect: 368, 706, 375, 715 ActionDest: 131 Annotation: Subtype: Link Rect: 378, 706, 385, 715 ActionDest: 131 Annotation: Subtype: Link Rect: 497, 681, 504, 690 ActionDest: 131 Annotation: Subtype: Link Rect: 504, 681, 511, 690 ActionDest: 131 Annotation: Subtype: Link Rect: 549, 668, 556, 677 ActionDest: 131 Annotation: Subtype: Link Rect: 361, 555, 368, 564 ActionDest: 131 Annotation: Subtype: Link Rect: 467, 518, 474, 526 ActionDest: 131 Annotation: Subtype: Link Rect: 294, 480, 301, 489 ActionDest: 131 Annotation: Subtype: Link Rect: 217, 455, 224, 464 ActionDest: 131 Annotation: Subtype: Link Rect: 228, 442, 235, 451 ActionDest: 131 Annotation: Subtype: Link Rect: 314, 417, 321, 426 ActionDest: 131 Annotation: Subtype: Link Rect: 308, 392, 320, 401 ActionDest: 134 Annotation: Subtype: Link Rect: 208, 379, 220, 388 ActionDest: 134 Annotation: Subtype: Link Rect: 532, 342, 544, 351 ActionDest: 134 Annotation: Subtype: Link Rect: 544, 342, 556, 351 ActionDest: 134 Annotation: Subtype: Link Rect: 200, 326, 207, 338 ActionDest: 73 Annotation: Subtype: Link Rect: 447, 304, 454, 313 ActionDest: 131 Annotation: Subtype: Link Rect: 255, 279, 267, 288 ActionDest: 134 Annotation: Subtype: Link Rect: 186, 254, 193, 263 ActionDest: 131 Annotation: Subtype: Link Rect: 425, 229, 432, 238 ActionDest: 131 Annotation: Subtype: Link Rect: 544, 204, 556, 213 ActionDest: 134 Annotation: Subtype: Link Rect: 235, 166, 247, 175 ActionDest: 134 Annotation: Subtype: Link Rect: 247, 166, 259, 175 ActionDest: 134 Annotation: Subtype: Link Rect: 260, 166, 272, 175 ActionDest: 134 Annotation: Subtype: Link Rect: 347, 154, 359, 162 ActionDest: 134 Annotation: Subtype: Link Rect: 360, 154, 372, 162 ActionDest: 134 Annotation: Subtype: Link Rect: 404, 141, 416, 150 ActionDest: 134 Annotation: Subtype: Link Rect: 417, 141, 429, 150 ActionDest: 134 Annotation: Subtype: Link Rect: 498, 141, 510, 150 ActionDest: 134 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 217, 327, 229, 336 ActionDest: 134 Annotation: Subtype: Link Rect: 401, 314, 413, 323 ActionDest: 134 Annotation: Subtype: Link Rect: 241, 72, 248, 84 ActionDest: 107 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 268, 641, 275, 652 ActionDest: 107 Annotation: Subtype: Link Rect: 458, 615, 465, 627 ActionDest: 110 Annotation: Subtype: Link Rect: 495, 605, 507, 614 ActionDest: 134 Annotation: Subtype: Link Rect: 508, 605, 519, 614 ActionDest: 134 Annotation: Subtype: Link Rect: 522, 605, 534, 614 ActionDest: 134 Annotation: Subtype: Link Rect: 458, 542, 470, 552 ActionDest: 134 Annotation: Subtype: Link Rect: 470, 543, 482, 552 ActionDest: 134 Annotation: Subtype: Link Rect: 483, 542, 495, 552 ActionDest: 134 Annotation: Subtype: Link Rect: 498, 542, 509, 552 ActionDest: 137 Annotation: Subtype: Link Rect: 549, 515, 556, 527 ActionDest: 110 Annotation: Subtype: Link Rect: 497, 427, 504, 439 ActionDest: 73 Annotation: Subtype: Link Rect: 549, 427, 556, 439 ActionDest: 110 Annotation: Subtype: Link Rect: 430, 326, 436, 338 ActionDest: 73 Annotation: Subtype: Link Rect: 482, 326, 489, 338 ActionDest: 110 Annotation: Subtype: Link Rect: 329, 289, 336, 301 ActionDest: 107 Annotation: Subtype: Link Rect: 356, 289, 362, 301 ActionDest: 110 Annotation: Subtype: Link Rect: 419, 263, 426, 275 ActionDest: 110 Annotation: Subtype: Link Rect: 468, 238, 475, 250 ActionDest: 110 Annotation: Subtype: Link Rect: 501, 213, 508, 225 ActionDest: 110 Page: Sequence: 5 Page: Sequence: 6 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 302, 469, 308, 479 ActionDest: 107 Annotation: Subtype: Link Rect: 436, 450, 445, 457 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 442, 445, 449 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 410, 445, 417 ActionDest: 134 Annotation: Subtype: Link Rect: 572, 410, 581, 417 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 394, 445, 401 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 386, 445, 393 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 378, 445, 385 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 370, 445, 377 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 362, 445, 369 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 354, 445, 361 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 346, 445, 353 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 338, 445, 345 ActionDest: 134 Annotation: Subtype: Link Rect: 572, 338, 581, 345 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 330, 445, 337 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 322, 445, 329 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 306, 445, 313 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 286, 445, 293 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 274, 445, 281 ActionDest: 134 Annotation: Subtype: Link Rect: 572, 274, 581, 280 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 266, 445, 273 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 246, 445, 253 ActionDest: 134 Annotation: Subtype: Link Rect: 572, 245, 581, 252 ActionDest: 137 Annotation: Subtype: Link Rect: 436, 218, 445, 225 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 210, 445, 217 ActionDest: 134 Annotation: Subtype: Link Rect: 572, 209, 581, 216 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 202, 445, 208 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 193, 445, 200 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 185, 445, 192 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 177, 445, 184 ActionDest: 134 Annotation: Subtype: Link Rect: 436, 154, 445, 161 ActionDest: 134 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 194, 650, 201, 662 ActionDest: 107 Annotation: Subtype: Link Rect: 271, 587, 278, 599 ActionDest: 107 Annotation: Subtype: Link Rect: 419, 524, 426, 536 ActionDest: 107 Annotation: Subtype: Link Rect: 250, 461, 257, 473 ActionDest: 73 Annotation: Subtype: Link Rect: 304, 461, 311, 473 ActionDest: 107 Annotation: Subtype: Link Rect: 392, 414, 404, 423 ActionDest: 134 Annotation: Subtype: Link Rect: 245, 401, 257, 410 ActionDest: 134 Annotation: Subtype: Link Rect: 337, 389, 349, 398 ActionDest: 137 Annotation: Subtype: Link Rect: 443, 389, 455, 398 ActionDest: 137 Annotation: Subtype: Link Rect: 465, 311, 472, 323 ActionDest: 110 Annotation: Subtype: Link Rect: 232, 273, 239, 285 ActionDest: 110 Annotation: Subtype: Link Rect: 402, 263, 414, 272 ActionDest: 134 Annotation: Subtype: Link Rect: 400, 250, 412, 260 ActionDest: 134 Annotation: Subtype: Link Rect: 194, 238, 206, 247 ActionDest: 134 Annotation: Subtype: Link Rect: 388, 226, 400, 234 ActionDest: 134 Annotation: Subtype: Link Rect: 454, 213, 466, 222 ActionDest: 137 Annotation: Subtype: Link Rect: 349, 188, 361, 197 ActionDest: 137 Annotation: Subtype: Link Rect: 211, 125, 223, 134 ActionDest: 134 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 415, 744, 427, 752 ActionDest: 134 Annotation: Subtype: Link Rect: 428, 743, 440, 752 ActionDest: 134 Annotation: Subtype: Link Rect: 440, 743, 452, 752 ActionDest: 134 Annotation: Subtype: Link Rect: 531, 718, 543, 727 ActionDest: 134 Annotation: Subtype: Link Rect: 544, 718, 556, 727 ActionDest: 134 Annotation: Subtype: Link Rect: 521, 665, 528, 677 ActionDest: 107 Annotation: Subtype: Link Rect: 549, 665, 556, 677 ActionDest: 110 Annotation: Subtype: Link Rect: 549, 653, 556, 665 ActionDest: 110 Annotation: Subtype: Link Rect: 522, 631, 534, 639 ActionDest: 134 Annotation: Subtype: Link Rect: 442, 605, 454, 614 ActionDest: 134 Annotation: Subtype: Link Rect: 455, 605, 467, 614 ActionDest: 134 Annotation: Subtype: Link Rect: 467, 605, 479, 614 ActionDest: 134 Annotation: Subtype: Link Rect: 253, 565, 260, 577 ActionDest: 107 Annotation: Subtype: Link Rect: 280, 565, 287, 577 ActionDest: 110 Annotation: Subtype: Link Rect: 526, 568, 538, 577 ActionDest: 134 Annotation: Subtype: Link Rect: 544, 555, 556, 564 ActionDest: 134 Annotation: Subtype: Link Rect: 446, 439, 453, 451 ActionDest: 107 Annotation: Subtype: Link Rect: 314, 389, 321, 401 ActionDest: 107 Annotation: Subtype: Link Rect: 481, 327, 488, 338 ActionDest: 107 Annotation: Subtype: Link Rect: 311, 276, 318, 288 ActionDest: 107 Annotation: Subtype: Link Rect: 489, 116, 496, 125 ActionDest: 131 Annotation: Subtype: Link Rect: 549, 75, 556, 87 ActionDest: 107 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 279, 706, 291, 715 ActionDest: 137 Annotation: Subtype: Link Rect: 544, 693, 556, 702 ActionDest: 137 Annotation: Subtype: Link Rect: 276, 628, 283, 640 ActionDest: 107 Annotation: Subtype: Link Rect: 301, 605, 313, 614 ActionDest: 137 Annotation: Subtype: Link Rect: 535, 540, 542, 552 ActionDest: 107 Annotation: Subtype: Link Rect: 395, 530, 407, 539 ActionDest: 134 Annotation: Subtype: Link Rect: 260, 502, 267, 514 ActionDest: 107 Annotation: Subtype: Link Rect: 480, 505, 492, 514 ActionDest: 134 Annotation: Subtype: Link Rect: 318, 492, 330, 501 ActionDest: 137 Annotation: Subtype: Link Rect: 547, 467, 559, 476 ActionDest: 134 Annotation: Subtype: Link Rect: 164, 455, 176, 464 ActionDest: 134 Annotation: Subtype: Link Rect: 177, 455, 189, 464 ActionDest: 134 Annotation: Subtype: Link Rect: 435, 430, 447, 439 ActionDest: 134 Annotation: Subtype: Link Rect: 448, 430, 460, 439 ActionDest: 134 Annotation: Subtype: Link Rect: 531, 417, 543, 426 ActionDest: 134 Annotation: Subtype: Link Rect: 543, 417, 555, 426 ActionDest: 134 Annotation: Subtype: Link Rect: 460, 392, 472, 401 ActionDest: 134 Annotation: Subtype: Link Rect: 473, 392, 485, 401 ActionDest: 134 Annotation: Subtype: Link Rect: 228, 379, 240, 388 ActionDest: 134 Annotation: Subtype: Link Rect: 241, 379, 253, 388 ActionDest: 134 Annotation: Subtype: Link Rect: 250, 240, 262, 249 ActionDest: 137 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 316, 203, 328, 212 ActionDest: 137 Annotation: Subtype: Link Rect: 535, 188, 560, 200 Annotation: Subtype: Link Rect: 165, 176, 252, 188 Annotation: Subtype: Link Rect: 375, 178, 387, 187 ActionDest: 137 Annotation: Subtype: Link Rect: 446, 138, 558, 150 Annotation: Subtype: Link Rect: 281, 128, 293, 137 ActionDest: 137 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 245, 700, 412, 712 Annotation: Subtype: Link Rect: 296, 662, 421, 674 Annotation: Subtype: Link Rect: 544, 665, 556, 674 ActionDest: 137 Annotation: Subtype: Link Rect: 534, 650, 560, 662 Annotation: Subtype: Link Rect: 165, 637, 343, 649 Annotation: Subtype: Link Rect: 462, 640, 474, 649 ActionDest: 137 Annotation: Subtype: Link Rect: 474, 640, 486, 649 ActionDest: 137 Annotation: Subtype: Link Rect: 223, 612, 471, 624 Annotation: Subtype: Link Rect: 194, 602, 206, 611 ActionDest: 137 Annotation: Subtype: Link Rect: 457, 575, 560, 587 Annotation: Subtype: Link Rect: 165, 562, 252, 574 Annotation: Subtype: Link Rect: 526, 538, 560, 549 Annotation: Subtype: Link Rect: 165, 526, 363, 537 Annotation: Subtype: Link Rect: 240, 237, 277, 248 Annotation: Subtype: Link Rect: 59, 215, 96, 225 Annotation: Subtype: Link Rect: 421, 202, 459, 213 Annotation: Subtype: Link Rect: 108, 180, 146, 190 Annotation: Subtype: Link Rect: 108, 157, 146, 167 Annotation: Subtype: Link Rect: 407, 145, 445, 156 Annotation: Subtype: Link Rect: 282, 122, 319, 133 Annotation: Subtype: Link Rect: 206, 99, 244, 110 Annotation: Subtype: Link Rect: 329, 76, 366, 88 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 127, 707, 164, 718 Annotation: Subtype: Link Rect: 511, 695, 548, 706 Annotation: Subtype: Link Rect: 493, 672, 531, 683 Annotation: Subtype: Link Rect: 188, 650, 225, 660 Annotation: Subtype: Link Rect: 59, 615, 96, 625 Annotation: Subtype: Link Rect: 491, 591, 528, 602 Annotation: Subtype: Link Rect: 332, 568, 370, 579 Annotation: Subtype: Link Rect: 398, 545, 435, 556 Annotation: Subtype: Link Rect: 495, 522, 533, 533 Annotation: Subtype: Link Rect: 175, 489, 212, 499 Annotation: Subtype: Link Rect: 321, 453, 359, 464 Annotation: Subtype: Link Rect: 378, 419, 416, 430 Annotation: Subtype: Link Rect: 422, 419, 458, 430 Annotation: Subtype: Link Rect: 428, 396, 466, 407 Annotation: Subtype: Link Rect: 472, 396, 508, 407 Annotation: Subtype: Link Rect: 332, 361, 370, 372 Annotation: Subtype: Link Rect: 376, 361, 412, 372 Annotation: Subtype: Link Rect: 383, 338, 420, 349 Annotation: Subtype: Link Rect: 427, 338, 463, 349 Annotation: Subtype: Link Rect: 108, 305, 146, 315 Annotation: Subtype: Link Rect: 152, 305, 188, 315 Annotation: Subtype: Link Rect: 445, 281, 482, 292 Annotation: Subtype: Link Rect: 489, 281, 525, 292 Annotation: Subtype: Link Rect: 205, 247, 242, 257 Annotation: Subtype: Link Rect: 420, 223, 457, 234 Annotation: Subtype: Link Rect: 463, 223, 499, 234 Annotation: Subtype: Link Rect: 113, 190, 150, 200 Annotation: Subtype: Link Rect: 192, 166, 229, 177 Annotation: Subtype: Link Rect: 470, 143, 508, 154 Annotation: Subtype: Link Rect: 514, 143, 550, 154 Annotation: Subtype: Link Rect: 478, 120, 515, 131 Annotation: Subtype: Link Rect: 521, 120, 557, 131 Annotation: Subtype: Link Rect: 398, 97, 435, 108 Annotation: Subtype: Link Rect: 441, 97, 477, 108 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 366, 718, 404, 729 Annotation: Subtype: Link Rect: 410, 718, 446, 729 Annotation: Subtype: Link Rect: 340, 683, 378, 694 Annotation: Subtype: Link Rect: 384, 683, 420, 694 Annotation: Subtype: Link Rect: 479, 660, 516, 671 Annotation: Subtype: Link Rect: 521, 660, 557, 671 Annotation: Subtype: Link Rect: 217, 626, 255, 637 Annotation: Subtype: Link Rect: 261, 626, 297, 637 Annotation: Subtype: Link Rect: 59, 592, 96, 602 Annotation: Subtype: Link Rect: 404, 534, 442, 545 Annotation: Subtype: Link Rect: 455, 499, 493, 510 Annotation: Subtype: Link Rect: 499, 499, 535, 510 Annotation: Subtype: Link Rect: 109, 466, 146, 476 Annotation: Subtype: Link Rect: 152, 466, 188, 476 Annotation: Subtype: Link Rect: 470, 442, 508, 453 Annotation: Subtype: Link Rect: 59, 408, 96, 418 Annotation: Subtype: Link Rect: 102, 408, 138, 418 Annotation: Subtype: Link Rect: 264, 385, 301, 395 Annotation: Subtype: Link Rect: 242, 362, 280, 372 Checksum: 443ff19d Type: CRC32 Checksum: 0e0f3ee62e8b58568088d9d330b1b55c Type: MD5 Checksum: f2f9f92d25e2118a3b2d206032257e14672ff6c6 Type: SHA-1 Checksum: 54cda2ca9f7dc6c2e979734800e69ecfacf960454500b4e470d8bc3b85d2c547 Type: SHA-256