US 20170009296A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0009296A1 Glessner et al. (43) Pub. Date: Jan. 12, 2017 (54) ASSOCIATION OF RARE RECURRENT (60) Provisional application No. 61/376.498, filed on Aug. GENETIC VARATIONS TO 24, 2010, provisional application No. 61/466,657, ATTENTION-DEFICIT, HYPERACTIVITY filed on Mar. 23, 2011. DISORDER (ADHD) AND METHODS OF USE THEREOF FOR THE DAGNOSS AND TREATMENT OF THE SAME Publication Classification (71) Applicant: The Children's Hospital of Philadelphia, Philadelphia, PA (US) (51) Int. Cl. CI2O I/68 (2006.01) (72) Inventors: Joseph Glessner, Mullica Hill, NJ A63L/454 (2006.01) (US); Josephine Elia, Penllyn, PA (52) U.S. Cl. (US); Hakon Hakonarson, Malvern, CPC ........... CI2O I/6883 (2013.01); A61 K3I/454 PA (US) (2013.01); C12O 2600/156 (2013.01); C12O (21) Appl. No.: 15/063,482 2600/16 (2013.01) (22) Filed: Mar. 7, 2016 Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 13/776,662, filed on Feb. 25, 2013, now abandoned, which is a continu ation-in-part of application No. PCT/US 11/48993, Compositions and methods for the detection and treatment filed on Aug. 24, 2011. of ADHD are provided. Patent Application Publication Jan. 12, 2017. Sheet 1 of 18 US 2017/000929.6 A1 Figure 1A ADHD Cases and Parentsi Siblings O SO Samples8 O 1. 1. 250C 40 gE 520 - Samples 3. Figure 1B Patent Application Publication Jan. 12, 2017. Sheet 2 of 18 US 2017/000929.6 A1 S&s sess'. ; S&s' ' Ny erre 8 Y-8 W - - 8 - - - - 8 - W - 8-8- W - 8 w w W & . ss --------SS is . 3.xx s S. tes. s v aas - ste. SS3, SSS 3. - - - ge (xxs wa. M& « » - - - -s &&. sš- or... & ss.S. Š. & & s. s: S- -: s: S- & SSS. SSS W SNS six&is-S ves Šs -$$$$$. 3.: . r S. Š es. & . $ . .- s & & ES & & & wx 8-. 3. & : --& Patent Application Publication Jan. 12, 2017. 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US 2017/000929.6 A1 Jan. 12, 2017 ASSOCATION OF RARE RECURRENT diagnosis and provide avenues for the development of GENETIC VARATIONS TO therapeutic agents having efficacy for the treatment of ATTENTION-DEFICIT, HYPERACTIVITY ADHD. DISORDER (ADHD) AND METHODS OF USE THEREOF FOR THE DAGNOSIS AND SUMMARY OF THE INVENTION TREATMENT OF THE SAME 0006. In accordance with the present invention, methods 0001. This application is a continuation of U.S. applica are provided for the diagnosis and treatment of ADHD. An tion Ser. No. 13/776,662 filed Feb. 25, 2013, which is a exemplary method entails detecting the presence of at least continuation in part of PCT/US2011/048993 filed Aug. 24, one CNV in a target polynucleotide wherein if said CNV(s) 2011 which in turn claims priority to U.S. Provisional is/are present, said patient has an increased risk for devel Applications 61/376.498 and 61/466,657 filed Aug. 24, 2010 oping ADHD. and Mar. 23, 2011 respectively, the entire contents of each 0007. In one aspect of the present invention, a method for being incorporated by reference as though set forth in full. detecting a propensity for developing attention deficit hyper activity disorder (ADHD) in a patient in need thereof is provided. An exemplary method entails detecting the pres FIELD OF THE INVENTION ence of at least 1, 2, 3, 4, 5, 6, 10, 20, 30 or all of the SNP 0002 This invention relates to the fields of genetics and containing nucleic acid in a target polynucleotide, said SNP the diagnosis of attention deficit hyperactivity disorder being informative of the presence of an ADHD associated (ADHD). More specifically, the invention provides compo copy number variation (CNV), wherein if said SNP is sitions and methods useful for the diagnosis and treatment of present, said patient has an increased risk for developing ADHD. ADHD, wherein said SNP containing nucleic acid is pro vided in Table 13. 0008. In another embodiment of the invention a method BACKGROUND OF THE INVENTION for identifying agents which alter neuronal signaling and/or 0003. Several publications and patent documents are morphology is provided. Such a method comprises provid cited through the specification in order to describe the state ing cells expressing at least one nucleic acid comprising the of the art to which this invention pertains. Each of these ADHD associated CNVs of the invention, (step a); provid citations is incorporated herein by reference as though set ing cells which express the cognate wild type sequences forth in full. which lack the CNV (step b); contacting the cells from each sample with a test agent and analyzing whether said agent 0004 Attention Deficit Hyperactivity Disorder (ADHD) alters neuronal signaling and/or morphology of cells of step is a common neuropsychiatric disorder with heritability a) relative to those of step b), thereby identifying agents estimates ranging from 30 to 90% (Derks, et al. 2008; Wood, which alter neuronal signaling and morphology. In a pre et al. 2008; Haberstic, et al. 2008). Most neurodevelopmen ferred embodiment the test agent modulates metabotropic tal disorders have been resistant to the genome wide asso glutamate receptor (mGluR) gene activity. In another ciation (GWA) approach, although recent progress has been embodiment the test agent is selected from a group consist made in autism (Glessner, et al. 2009: Derks, et al. 2008: ing of an mGluR positive allosteric modulators (PAM) (e.g., Wod, et al. 2008; Haberstic, et al. 2008: Wang, et al. 2009). mGluR5 PAM, mGluR7 PAM), an mGluR negative allos GWA studies have been reported in ADHD utilizing a cohort teric modulator (NAM) (e.g., mGluR2/3 NAM), and a of 958 parent-child trios recruited through the International tachykinin-3/neurokinin-3 receptor (TAC3/NK3R) antago Multicentre ADHD Genetics (IMAGE) study.