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US 20160281 166A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0281166 A1 BHATTACHARJEE et al. (43) Pub. Date: Sep. 29, 2016 (54) METHODS AND SYSTEMIS FOR SCREENING Publication Classification DISEASES IN SUBJECTS (51) Int. Cl. (71) Applicant: PARABASE GENOMICS, INC., CI2O I/68 (2006.01) Boston, MA (US) C40B 30/02 (2006.01) (72) Inventors: Arindam BHATTACHARJEE, G06F 9/22 (2006.01) Andover, MA (US); Tanya (52) U.S. Cl. SOKOLSKY, Cambridge, MA (US); CPC ............. CI2O 1/6883 (2013.01); G06F 19/22 Edwin NAYLOR, Mt. Pleasant, SC (2013.01); C40B 30/02 (2013.01); C12O (US); Richard B. PARAD, Newton, 2600/156 (2013.01); C12O 2600/158 MA (US); Evan MAUCELI, (2013.01) Roslindale, MA (US) (21) Appl. No.: 15/078,579 (57) ABSTRACT (22) Filed: Mar. 23, 2016 Related U.S. Application Data The present disclosure provides systems, devices, and meth (60) Provisional application No. 62/136,836, filed on Mar. ods for a fast-turnaround, minimally invasive, and/or cost 23, 2015, provisional application No. 62/137,745, effective assay for Screening diseases, such as genetic dis filed on Mar. 24, 2015. orders and/or pathogens, in Subjects. Patent Application Publication Sep. 29, 2016 Sheet 1 of 23 US 2016/0281166 A1 SSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS S{}}\\93? sau36 Patent Application Publication Sep. 29, 2016 Sheet 2 of 23 US 2016/0281166 A1 &**** ? ???zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz??º & %&&zzzzzzzzzzzzzzzzzzzzzzz &Sssssssssssssssssssssssssssssssssssssssssssssssssssssssss & s s sS ------------------------------ Patent Application Publication Sep. 29, 2016 Sheet 3 of 23 US 2016/0281166 A1 23 25 20 FG, 2. Patent Application Publication Sep. 29, 2016 Sheet 4 of 23 US 2016/0281166 A1 : S Patent Application Publication Sep. 29, 2016 Sheet 5 of 23 US 2016/0281166 A1 - BS 25 SO Six F.G. 44 Patent Application Publication Sep. 29, 2016 Sheet 6 of 23 US 2016/0281166 A1 %. FG, 4 B Patent Application Publication Sep. 29, 2016 Sheet 7 of 23 US 2016/0281166 A1 {{Citi sexy-w yes werex xwyx 8.8 S.S. s 3: 8 sws: ixx 88: 1 | Ex. | & s Š. se Patent Application Publication Sep. 29, 2016 Sheet 9 of 23 US 2016/0281166 A1 is : x.ŠNSWNSSoxxs S. S$\ SS ^s. w Šss xsm : ES išYi'3: $888. Six:3: F.G. C. Patent Application Publication Sep. 29, 2016 Sheet 10 of 23 US 2016/0281166 A1 450000 prior 400000 in us WES 350000 383 . ::: Patent Application Publication Sep. 29, 2016 Sheet 11 of 23 US 2016/0281166 A1 B F.G. 6B Patent Application Publication Sep. 29, 2016 Sheet 12 of 23 US 2016/0281166 A1 Fassig is Fitters? * Protein impact e Aki faiiar: * Regis g Acq::se Zygosity is is: casgos at 38-83% of eac{s} ataxiase • variet Scoring Annotation Known polymorphism or predicted is rigin? Honozygous? (“ -: Ritai: ineface? ------------------------------------------------------ Sisectei isieterious base on No variant type of grediction algorithis? Yes Yes of 33 ygosioi ecessive disease geste & co;i&st site;t&ea? sS *Yes. Sompositi heterozygote with 88 2 is etects statis? F.C. 7 Patent Application Publication Sep. 29, 2016 Sheet 13 of 23 US 2016/0281166 A1 &pixes sixirst & S 8 if is-Seasies is Eat's as SS k is six S-SE expies & $ r. s s^YsaxxxWSWSWWWWWSWWWWWSWWWsixs 888 S. $88: Si: 88 Siges:8888 is {xy}ssfs&&. Patent Application Publication Sep. 29, 2016 Sheet 15 of 23 US 2016/0281166 A1 & Patent Application Publication Sep. 29, 2016 Sheet 17 of 23 US 2016/0281166 A1 A. six x: 8xxx x: FIG. I. IA Patent Application Publication Sep. 29, 2016 Sheet 18 of 23 US 2016/0281166 A1 : : : : S g : : S Patent Application Publication Sep. 29, 2016 Sheet 19 of 23 US 2016/0281166 A1 l Exome t is exixxx xxxx FIG. I.3 Patent Application Publication Sep. 29, 2016 Sheet 20 of 23 US 2016/0281166 A1 FC, i. Patent Application Publication Sep. 29, 2016 Sheet 21 of 23 US 2016/0281166 A1 Patent Application Publication Sep. 29, 2016 Sheet 22 of 23 US 2016/0281166 A1 C3A&G 33 & C SCCs F.G. 64 Patent Application Publication Sep. 29, 2016 Sheet 23 of 23 US 2016/0281166 A1 BTD OGCDH OGALT FIG. I.6B US 2016/0281166 A1 Sep. 29, 2016 METHODS AND SYSTEMIS FOR SCREENING sample, a cord blood sample, single blood drop, saliva, oral DISEASES IN SUBJECTS swab, other body fluid or other tissue; (b) sequencing the sample to generate a sequencing product, wherein the CROSS-REFERENCE sequencing product is determined by a sequencing method selected from a group consisting of next-generation 0001. This application claims priority to U.S. Provisional sequencing (NGS), targeted next-generation sequencing Patent Application 62/136,836, filed Mar. 23, 2015, and U.S. (TNGS) and whole-exome sequencing (WES); and (c) ana Provisional Patent Application 62/137,745, filed Mar. 24, lyzing the sequencing product to determine a presence of 2015, which are entirely incorporated herein by reference. absence of or predisposition to the pathogen. In some cases, GOVERNMENT RIGHTS the methods and systems further comprise providing a sample previously obtained from a relative of the subject. 0002. The invention described herein was made with 0007. The methods and systems disclosed herein can also government support under phase I SBIR NIH grants from be used for detecting a hearing loss condition in a Subject, NIDCD (1R43DC013012-01) and NICHD comprising: (a) providing a sample previously obtained (1R43HD076544-01) awarded by the National Institutes of from the Subject, wherein the sample comprises a dried Health. The United States Government has certain rights in blood spot (DBS) sample, a cord blood sample, single blood the invention. drop, saliva, oral Swab, other body fluid or other tissue; (b) sequencing the sample to generate a sequencing product, BACKGROUND wherein the sequencing product is determined by a sequenc 0003 For newborns with genetic disorders, a rapid diag ing method selected from a group consisting of next-gen nosis of diseases can make the difference between life and eration sequencing (NGS), targeted next-generation death and reduce length of stay in the neonatal intensive care sequencing (TNGS) and whole-exome sequencing (WES); unit (NICU). However, current single gene sequencing and (c) analyzing the sequencing product to determine a methods used for confirmatory diagnosis can be impractical presence of absence of or predisposition to the hearing loss in newborns. They can be costly, time consuming and condition. In some cases, the methods and systems further require a large blood Volume that cannot be easily or safely comprise providing a sample previously obtained from a obtained from an infant. relative of the subject. 0004 Two compelling forces are expected to drive adop 0008. In an aspect, the subject disclosed herein is a fetus, tion of genetic testing in newborns. First is the need for a newborn, an infant, a child, an adolescent, a teenager or an rapid, minimally invasive diagnosis to treat and minimize adult. In some cases, the Subject is a newborn. In some cases, adverse outcomes. Second is the financial incentive to the subject is within 28 days after birth. In some cases, the shorten length of stay and reduce overall patient-manage subject is a relative of a newborn. ment costs associated with delayed or inaccurate diagnosis. 0009. In another aspect, the methods and systems dis The methods and systems disclosed herein can provide a closed herein use less than 1000 uL of the sample (e.g. fast-turnaround, minimally invasive, and cost-effective DBS). For example, less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, assay for Screening diseases, such as genetic disorders 30, 40, 50, 60, 70, 80,90, 100, 150, 200, 250, 300, 350, 400, and/or pathogens, in newborns. It demonstrates that turn 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or around and sample requirements for newborn genetic cases 1000 uL of the sample (e.g. DBS) can be used. can be achieved using Targeted Next-Generation Sequenc 0010. In another aspect, the sample disclosed herein is a ing (TNGS), and that combining genetic etiology (via blood sample. In some cases, the blood sample is a dried TNGS) with phenotype can allow a prompt and comprehen blood spot (DBS) sample. In some cases, the sample con sive clinical understanding. tains less than 1000 uL of blood. For example, less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, SUMMARY 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 0005. The methods and systems disclosed herein can be 750, 800, 850,900, 950 or 1000 uL of the sample (e.g. DBS) used for detecting a genetic condition in a Subject, compris is contained within the sample. In some cases, the sample ing: (a) providing a sample previously obtained from the contains less than 50 uL of blood. Subject, wherein the sample comprises a dried blood spot 0011. In another aspect, providing a sample further com (DBS) sample, a cord blood sample, single blood drop, prise purifying and/or isolating a DNA from the sample. In saliva, oral swab, other bodily fluid or other tissue; (b) another aspect, providing a sample does not comprise puri sequencing the sample to generate a sequencing product, fying and/or isolating a DNA from the sample. In some wherein the sequencing product is determined by a sequenc cases, the sample is a whole blood sample. In some cases, ing method selected from a group consisting of next-gen the sample is a whole blood sample without purification. In eration sequencing (NGS), targeted next-generation Some cases, the sample is a purified sample.
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  • Genes in Eyecare Geneseyedoc 3 W.M

    Genes in Eyecare Geneseyedoc 3 W.M

    Genes in Eyecare geneseyedoc 3 W.M. Lyle and T.D. Williams 15 Mar 04 This information has been gathered from several sources; however, the principal source is V. A. McKusick’s Mendelian Inheritance in Man on CD-ROM. Baltimore, Johns Hopkins University Press, 1998. Other sources include McKusick’s, Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders. Baltimore. Johns Hopkins University Press 1998 (12th edition). http://www.ncbi.nlm.nih.gov/Omim See also S.P.Daiger, L.S. Sullivan, and B.J.F. Rossiter Ret Net http://www.sph.uth.tmc.edu/Retnet disease.htm/. Also E.I. Traboulsi’s, Genetic Diseases of the Eye, New York, Oxford University Press, 1998. And Genetics in Primary Eyecare and Clinical Medicine by M.R. Seashore and R.S.Wappner, Appleton and Lange 1996. M. Ridley’s book Genome published in 2000 by Perennial provides additional information. Ridley estimates that we have 60,000 to 80,000 genes. See also R.M. Henig’s book The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, published by Houghton Mifflin in 2001 which tells about the Father of Genetics. The 3rd edition of F. H. Roy’s book Ocular Syndromes and Systemic Diseases published by Lippincott Williams & Wilkins in 2002 facilitates differential diagnosis. Additional information is provided in D. Pavan-Langston’s Manual of Ocular Diagnosis and Therapy (5th edition) published by Lippincott Williams & Wilkins in 2002. M.A. Foote wrote Basic Human Genetics for Medical Writers in the AMWA Journal 2002;17:7-17. A compilation such as this might suggest that one gene = one disease.