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US 201602897.62A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0289762 A1 KOH et al. (43) Pub. Date: Oct. 6, 2016 (54) METHODS FOR PROFILIING AND Publication Classification QUANTITATING CELL-FREE RNA (51) Int. Cl. (71) Applicant: The Board of Trustees of the Leland CI2O I/68 (2006.01) Stanford Junior University, Palo Alto, (52) U.S. Cl. CA (US) CPC ....... CI2O 1/6883 (2013.01); C12O 2600/112 (2013.01); C12O 2600/118 (2013.01); C12O (72) Inventors: Lian Chye Winston KOH, Stanford, 2600/158 (2013.01) CA (US); Stephen R. QUAKE, Stanford, CA (US); Hei-Mun Christina FAN, Fremont, CA (US); Wenying (57) ABSTRACT PAN, Stanford, CA (US) The invention generally relates to methods for assessing a (21) Appl. No.: 15/034,746 neurological disorder by characterizing circulating nucleic acids in a blood sample. According to certain embodiments, (22) PCT Filed: Nov. 6, 2014 methods for S. a Nial disorder include (86). PCT No.: PCT/US2O14/064355 obtaining RNA present in a blood sample of a patient Suspected of having a neurological disorder, determining a S 371 (c)(1), level of RNA present in the sample that is specific to brain (2) Date: May 5, 2016 tissue, comparing the sample level of RNA to a reference O O level of RNA specific to brain tissue, determining whether a Related U.S. Application Data difference exists between the sample level and the reference (60) Provisional application No. 61/900,927, filed on Nov. level, and indicating a neurological disorder if a difference 6, 2013. is determined. Patent Applica US 2016/02897.62 A1 Patent Application Publication Oct. 6, 2016 Sheet 2 of 37 US 2016/02897.62 A1 0000|| 000G ?.Od 0000G-0000|- 000G 000G Patent Application Publication US 2016/02897.62 A1 Patent Application Publication Oct. 6, 2016 Sheet 4 of 37 US 2016/02897.62 A1 Patent Application Publication Oct. 6, 2016 Sheet 7 of 37 US 2016/02897.62 A1 Ranking by Significance Gene Name 5 HIST1H4B 6 TREML.1 7 NPTN 8 LSM2 SCGB1C1 NOP10 MFSD1 MALAT1 GDI1 HIST1H1C HIST1H4H CD226 FIG. 4 Patent Application Publication Oct. 6, 2016 Sheet 9 of 37 US 2016/02897.62 A1 SEINE5)Ol=|13)EdSENTISSILHONOI_L\/OI=I_LNEIGII 5DNIHOLVINEILV/Tc||NELL'], TO?|LNOOALITVITO"Z |SEITCHINVSOIHIDEICHSEITISSIL Patent Application Publication Oct. 6, 2016 Sheet 11 of 37 US 2016/02897.62 A1 ºnSSIL IOXOqpeQUDIJOJ 3uueNIInHºu05) ZQUOUJOU,U?AAOJ?ZHR) A. O 9 Patent Application Publication Oct. 6, 2016 Sheet 12 of 37 US 2016/02897.62 A1 ejuºseI,IgJequêu‘KIIULIEJ9XIII-XINILNpubLITS ZVN5) 9IIRIGIÐ (HdHAO 18.L^IXI |OZHOHIA INIAI RIIAdAN IRISJLN IZVO LOSd. ©IGHÈO,LAI CHOHRI Z{{JLVS LVNI«TRICHS ?XIRILITIS Patent Application Publication Oct. 6, 2016 Sheet 13 of 37 US 2016/0289762 A1 FIG. 9A Example of raw qPCR data for fetal brain transcript ZNF238 obtained from subject sample P53 shows the changes across the three trimesters & post-partum. Amplification É Patent Application Publication Oct. 6, 2016 Sheet 14 of 37 US 2016/02897.62 A1 FIG. 9B Example of raw qPCR data for fetal brain transcript ZNF238 obtained from subject sample P53 shows the melting curve of the same experiments of 9A. Melting O.40 0.38 O.36. 0.34 0.32. O3O 0.28 0.26 0.24. 0.22 O20 O. 18. 0.16. 0.14 0.12 O 1 O. O.O8. OO6 0.04 0.02 as 0.00k -0.02 -0.04. -0.06 Temperature Patent Application Publication Oct. 6, 2016 Sheet 15 of 37 US 2016/02897.62 A1 c {efuse of Patent Application Publication Oct. 6, 2016 Sheet 16 of 37 US 2016/02897.62 A1 (8 ft. e. g.o. Patent Application Publication Oct. 6, 2016 Sheet 17 of 37 US 2016/02897.62 A1 3. 8) Rico v v CD Patent Application Publication Oct. 6, 2016 Sheet 18 of 37 US 2016/02897.62 A1 ZXTG|GOTW ZEIVS||HSLN INWIZVN9||ZXTG|GOTVO on O efuel picio Patent Application Publication Oct. 6, 2016 Sheet 19 of 37 US 2016/02897.62 A1 (eiti e de Patent Application Publication Oct. 6, 2016 Sheet 20 of 37 US 2016/02897.62 A1 ZXTO XOO & Rei 20 Patent Application Publication Oct. 6, 2016 Sheet 21 of 37 US 2016/0289762 A1 Figure 3. i-eative Caposition of different orga:8 coiiriisitioi towaris piasinia ceilies: transcript 313& ig ire 4, ac{{np}{38iticis of {}rgan citrit::tio towards ce: free transcripton: 3:iig. 3 NA-se: sia: Patent Application Publication Oct. 6, 2016 Sheet 23 of 37 US 2016/0289762 A1 Detecting a Sample level of RNA in a Biological Sample Comparing the Sample Level of RNA to a Reference eve of RNA Determining Whether a Difference Exists Between the Sample Level and the Reference Level Characterizing the Tissue as Abnormal if a Difference is Detected FIG. 16 Patent Application Publication US 2016/02897.62 A1 casa s ? F.G. 17 Patent Application Publication Oct. 6, 2016 Sheet 25 of 37 US 2016/02897.62 A1 Experimental Des gn SSS: &8 grass 8888g: * * : * Sists & Syst &sis: WY & ?r tiss E is firsa S. SSSSSSSSSSSSSSSSSSSSSSSSSSSSS s SSSSSSSSSSSSSSSSSSSSSSSSSSSSS stilized NFS pigeiste %?*** FIG. 18 Patent Application Publication Oct. 6, 2016 Sheet 26 of 37 US 2016/02897.62 A1 Temporal varying Genes FIG. 19 Patent Application Publication Oct. 6, 2016 Sheet 27 of 37 US 2016/0289762 A1 & S. & 83. W S. $8& ::ssssss & S. Patent Application Publication Oct. 6, 2016 Sheet 28 of 37 US 2016/02897.62 A1 % s Ssss & &w8 s |uo?anqunuopmenad Patent Application Publication Oct. 6, 2016 Sheet 29 of 37 US 2016/0289762 A1 S. S Sss XXX SSXX S.& S. S.& Patent Application Publication Oct. 6, 2016 Sheet 30 of 37 US 2016/0289762 A1 Patent Application Publication Oct. 6, 2016 Sheet 31 of 37 US 2016/0289762 A1 | & S. & $& S.$ S.S S & & & S & Patent Application Publication Oct. 6, 2016 Sheet 32 of 37 US 2016/02897.62 A1 ssie Cornpos ::: S. S. × FIG. 25 Patent Application Publication Oct. 6, 2016 Sheet 33 of 37 US 2016/02897.62 A1 Tissue Composition Subject Stject 2 Sigriseasis 2s Hypoala Sas iyiphthalasis : W Sisirisis: 888. Big: iaiti:8isitsis 3% ymphods Boneiaarow 3% &ryggaia 4% 3:3Rivisis is Sotite issues 3% iyiri is 38. 8:33,838. ge3.cxxiii.2% Sutject 3 Subject 4. gags: hygihaiaris & 8:33:31:3 is: lying:3ie 88. Broix:aEpiteia:Ceis 3% 88:38::3% Si:icists 8: Sysius.2% S$38, Sis itytrid 2% S sayings 3% FG. 26 Patent Application Publication Oct. 6, 2016 Sheet 34 of 37 US 2016/0289762 A1 m ississis & & FIG. 27 Patent Application Publication Oct. 6, 2016 Sheet 35 of 37 US 2016/0289762 A1 s S SSss & $8S : WW’ MWSS^^^^^^^^^^^^^^^^^^^W. SS 3.s S. s &SS S 8-X-XX-3---------------x-----------------------------& Patent Application Publication Oct. 6, 2016 Sheet 36 of 37 US 2016/02897.62 A1 SSS Patent Application Publication Oct. 6, 2016 Sheet 37 of 37 US 2016/0289762 A1 100 ,, sysS. sisSaaS s, AUC: O.79. S .. s: ... 0.50 o.75 Faise Fositive Rate FG. 3O US 2016/02897.62 A1 Oct. 6, 2016 METHODS FOR PROFLING AND circulating nucleic acid that are specific to brain tissue. The QUANTITATING CELL-FREE RNA present invention recognizes that abnormal deviations in circulating nucleic acid result from tissue-specific nucleic RELATED APPLICATIONS acid being released into the blood in large amounts as tissue 0001. This application claims the benefit of and priority begins to fail and degrade. By focusing on genes the to U.S. Provisional No. 61/900,927, filed Nov. 6, 2013, and expression of which is highly specific to brain tissue, meth is a continuation-in-part of U.S. Non-Provisional Ser. No. ods of the invention allow one to characterize the extent of 13/752,131, filed Jan. 28, 2013, which claims the benefit of brain degradation based on statistically-significant levels of and priority to U.S. Provisional No. 61/591,642, filed on Jan. circulating brain-specific transcripts; and use that character 27, 2012. The entirety of each foregoing application is ization to diagnose and determine the stage of the neuro incorporated herein by reference. logical disease. Accordingly, methods of the invention allow one to characterize neurological disorders without focusing TECHNICAL FIELD on Small Subset of known biomarkers, but rather focusing on the extent to which nucleic acid is released into blood from 0002 The present invention relates to assessing neuro brain tissue affected by disease. Methods of the invention are logical disorders based on nucleic acid specific to brain particularly useful in diagnosing and determining the stage tissue. of Alzheimer's disease. 0007. In particular embodiments, methods of the inven BACKGROUND tion include obtaining RNA from a blood sample of a patient 0003. Dementia is a catchall term used to characterize Suspected of having a neurological disorder, and determin cognitive declines that interfere with one’s ability to perform ing a level of the sample RNA that originated from brain everyday activities. Signs of dementia include declines in tissue. In certain embodiments, the RNA is converted to the following mental functions: memory, communication cDNA. The level of the sample RNA specific to brain tissue and language, ability to focus and pay attention, reasoning, is then compared to a reference level of RNA that is specific judgment, motor skills, and visual perception. While there to brain tissue. The reference level may be derived from a are several neurological disorders that cause dementia, Subject or patient population having a neurological disorder Alzheimer's disease is the most common, accounting for 60 or from a normal/control Subject or patient population.
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    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
  • REVIEW ARTICLE the Genetics of Autism

    REVIEW ARTICLE the Genetics of Autism

    REVIEW ARTICLE The Genetics of Autism Rebecca Muhle, BA*; Stephanie V. Trentacoste, BA*; and Isabelle Rapin, MD‡ ABSTRACT. Autism is a complex, behaviorally de- tribution of a few well characterized X-linked disorders, fined, static disorder of the immature brain that is of male-to-male transmission in a number of families rules great concern to the practicing pediatrician because of an out X-linkage as the prevailing mode of inheritance. The astonishing 556% reported increase in pediatric preva- recurrence rate in siblings of affected children is ϳ2% to lence between 1991 and 1997, to a prevalence higher than 8%, much higher than the prevalence rate in the general that of spina bifida, cancer, or Down syndrome. This population but much lower than in single-gene diseases. jump is probably attributable to heightened awareness Twin studies reported 60% concordance for classic au- and changing diagnostic criteria rather than to new en- tism in monozygotic (MZ) twins versus 0 in dizygotic vironmental influences. Autism is not a disease but a (DZ) twins, the higher MZ concordance attesting to ge- syndrome with multiple nongenetic and genetic causes. netic inheritance as the predominant causative agent. By autism (the autistic spectrum disorders [ASDs]), we Reevaluation for a broader autistic phenotype that in- mean the wide spectrum of developmental disorders cluded communication and social disorders increased characterized by impairments in 3 behavioral domains: 1) concordance remarkably from 60% to 92% in MZ twins social interaction; 2) language, communication, and and from 0% to 10% in DZ pairs. This suggests that imaginative play; and 3) range of interests and activities.
  • Haploinsufficiency of Cardiac Myosin Binding Protein-C in the Development of Hypertrophic Cardiomyopathy

    Haploinsufficiency of Cardiac Myosin Binding Protein-C in the Development of Hypertrophic Cardiomyopathy

    Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 2014 Haploinsufficiency of Cardiac Myosin Binding Protein-C in the Development of Hypertrophic Cardiomyopathy David Barefield Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Physiology Commons Recommended Citation Barefield, David, "Haploinsufficiency of Cardiac Myosin Binding Protein-C in the Development of Hypertrophic Cardiomyopathy" (2014). Dissertations. 1249. https://ecommons.luc.edu/luc_diss/1249 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 2014 David Barefield LOYOLA UNIVERSITY CHICAGO HAPLOINSUFFICIENCY OF CARDIAC MYOSIN BINDING PROTEIN-C IN THE DEVELOPMENT OF HYPERTROPHIC CARDIOMYOPATHY A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL IN CANDIDACY FOR THE DEGREE OF DOCTOR OF PHILOSOPHY PROGRAM IN CELL AND MOLECULAR PHYSIOLOGY BY DAVID YEOMANS BAREFIELD CHICAGO, IL AUGUST 2014 Copyright by David Yeomans Barefield, 2014 All Rights Reserved. ii ACKNOWLEDGEMENTS The completion of this work would not have been possible without the support of excellent mentors, colleagues, friends, and family. I give tremendous thanks to my mentor, Dr. Sakthivel Sadayappan, who has facilitated my growth as a scientist and as a human being over the past five years. I would like to thank my dissertation committee: Drs. Pieter de Tombe, Kenneth Byron, Leanne Cribbs, Kyle Henderson, and Christine Seidman for their erudite guidance of my project and my development as a scientist.