# US 2014/0155271 A1 · Methods and compositions for diagnosing, prognosing, and treating neurological conditions

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- Number: US 2014/0155271 A1
- Document ID: US20140155271A1
- Status: Published application
- Kind: A1
- Application number: 13/668,049
- Filed: 2012-11-02
- Published: 2014-06-05
- Earliest claimed: 2011-11-04
- Assignees: Population Diagnostics, Inc.; The Research Foundation of State University of New York
- Applicants: The Research Foundation of State of Univesity of New York
- Inventors: ELI HATCHWELL; PEGGY S. EIS
- Web page: https://patentgrep.com/patent/US20140155271A1

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12Q 1/6809: Methods for determination or identification of nucleic acids involving differential detection
- C12Q 1/6813: Hybridisation assays
- C12Q 1/6827: for detection of mutation or polymorphism
- C12Q 1/686: Polymerase chain reaction [PCR]
- C12Q 1/6869: Methods for sequencing
- G01N 33/5023: {on expression patterns}
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- G01N 33/48: Biological material, e.g. blood, urine (G01N33/02, G01N33/26, G01N33/44, G01N33/46 take precedence); Haemocytometers (counting blood corpuscules distributed over a surface by scanning the surface G06M11/02)
- G01N 33/5005: {involving human or animal cells (immunoassay G01N33/56966; immunoassays of protozoa G01N33/56905; protozoa in screening assays C12Q1/025)}
- G01N 33/5058: {Neurological cells}
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

This document provides methods and materials related to genetic variations of neurological disorders. For example, this document provides methods for using such genetic variations to assess susceptibility of developing Parkinson's disease.

## Claims

### Claim 1

A method of screening one or more subjects for at least one genetic variation comprising: assaying at least one nucleic acid sample obtained from each of the one or more subjects for the at least one genetic variation that disrupts or modulates one or more genes in Table 3.

### Claim 2 (depends on 1)

The method of claim 1, wherein the at least one genetic variation is associated with a neurological disorder (ND) or a movement disorder.

### Claim 3 (depends on 1)

The method of claim 1, wherein the at least one genetic variation is one encoded by any one of SEQ ID NOs 1 to 382.

### Claim 4 (depends on 1)

The method claim 1, wherein the at least one genetic variation comprises one or more point mutations, polymorphisms, translocations, insertions, deletions, amplifications, inversions, microsatellites, interstitial deletions, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), single nucleotide variations (SNVs), or any combination thereof, wherein the at least one genetic variation results in a loss or gain of gene function of the one or more genes in Table 3.

### Claim 5 (depends on 1)

The method of claim 1, wherein the at least one genetic variation disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020, or expression of an RNA transcript or polypeptide expressed therefrom.

### Claim 6

(canceled)

### Claim 7 (depends on 1)

The method of claim 1, wherein the assaying comprises detecting nucleic acid information from the at least one nucleic acid sample by one or more methods selected from the group consisting of PCR, sequencing, a Northern blot, amplification, hybridization, microarray analysis, or any combination thereof.

### Claim 8

(canceled)

### Claim 9 (depends on 7)

The method of claim 7, wherein the assaying is sequencing, and the sequencing comprises sequencing method selected from the group consisting of Massively Parallel Signature Sequencing (MPSS), polony sequencing, 454 bvrosequencing, Illumina sequencing, SOLiD sequencing, ion semiconductor sequencing, DNA nanoball sequencing, heliscope single molecule sequencing, single molecule real time (SMRT) sequencing, RNAP sequencing, Nanopore DNA sequencing, sequencing by hybridization, or microfluidic Sanger sequencing.

### Claim 10

(canceled)

### Claim 11 (depends on 1)

The method of claim 1, wherein the at least one nucleic acid sample is collected from blood, saliva, urine, serum, tears, skin, tissue, or hair from the one or more subjects.

### Claim 12 (depends on 1)

The method of claim 1, wherein the assaying the at least one nucleic acid sample of the one or more subjects comprises purifying nucleic acids from the at least one nucleic acid sample, and directly assaying one or more of the purified nucleic acids or amplifying a nucleotide sequence of the purified nucleic acids.

### Claim 13

(canceled)

### Claim 14

(canceled)

### Claim 15 (depends on 7)

The method of claim 7, wherein the assaying is the microarray analysis, and wherein the microarray analysis comprises a Comparative Genomic Hybridization (CGH) array analysis.

### Claim 16

(canceled)

### Claim 17 (depends on 1)

The method of claim 1, further comprising determining whether the one or more subjects has a ND, or an altered susceptibility to an ND.

### Claim 18 (depends on 1)

The method of claim 1, wherein the one or more subjects were previously diagnosed or are suspected as having the ND based on an evaluation by a medical doctor, a psychologist, a neurologist, a psychiatrist, or other professionals who screen subjects for an ND.

### Claim 19

(canceled)

### Claim 20 (depends on 17)

The method of claim 17, wherein the determining comprises an evaluation of the one or more subject's motor skills, autonomic function, neuropsychiatry, mood, cognition, behavior, thoughts, ability to sense, family history of early-onset-NDs or late-onset NDs, or a combination thereof.

### Claim 21

(canceled)

### Claim 22

(canceled)

### Claim 23 (depends on 1)

The method of claim 1, wherein the screening the one or more subjects further comprises selecting one or more therapies based on the presence or absence of the one or more genetic variations.

### Claim 24 (depends on 1)

The method of claim 1, wherein the assaying at least one nucleic acid sample obtained from each of the one or more subjects comprises analyzing the whole genome or whole exome from the one or more subjects.

### Claim 25 (depends on 1)

The method of claim 1, wherein the nucleic acid information has already been obtained for the whole genome or whole exome from the one or more individuals and the nucleic acid information is obtained from in silico analysis.

### Claim 26 (depends on 2)

The method of claim 2, wherein the ND is Parkinson's Disease (PD).

### Claim 27 (depends on 2)

The method of claim 2, wherein the one or more subjects have at least one symptom of the ND.

### Claim at position 28

-72. (canceled)

### Claim 73

A method of screening for a therapeutic agent for treatment of an ND, comprising identifying an agent that disrupts or modulates one or more genes in Table 3, one or more genomic sequences of SEQ ID NOs 383 to 1020, or one or more expression products thereof, wherein the one or more expression products thereof are selected from the group consisting of RNA transcripts and polypeptides.

### Claim 74 (depends on 73)

The method of claim 73, wherein the agent comprises a small molecule, polypeptide, polynucleotide, or a combination thereof.

### Claim 75 (depends on 73)

The method of claim 73, wherein the agent comprises a gene therapy agent, an exogenous polynucleotide comprising a gene, an agent that treats a subject in need of gene therapy, an agent that treats a subject with a deficiency in a polypeptide, or a combination thereof.

### Claim 76

(canceled)

### Claim 77

(canceled)

### Claim 78 (depends on 73)

The method of any one of claim 73, wherein the disrupting or modulating comprises an increase or decrease in expression of the one or more expression products.

### Claim at position 35

-84. (canceled)

### Claim 85 (depends on 73)

The method of claim 73, wherein the agent is selected from the group consisting of an antibody, one or more drugs, one or more compounds, radiation, one or more genetic sequences, heat, cryogenics, a vitamin, an antioxidant, a mineral, and any combination thereof.

### Claim at position 37

-90. (canceled)

### Claim 91

A kit for screening for an ND in one or more subjects, the kit comprising reagents for assaying a nucleic acid sample from the one or more subjects for the presence of at least one genetic variation encoded by any one of SEQ ID NOs 1-382, or at least one genetic variation that disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020 or expression of an RNA transcript or polypeptide expressed therefrom.

### Claim at position 39

-103. (canceled)

### Claim 104

An isolated polynucleotide sequence or fragment thereof, comprising at least 60% identity to any one of SEQ ID NOs 1 to 382 or a genetic variation that disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020, or a compliment thereof, wherein the isolated polynucleotide sequence, or fragment thereof, is hybridized to a synthetic oligonucleotide.

### Claim 105 (depends on 104)

The isolated polynucleotide sequence or fragment thereof, of claim 104, comprising at least 70% identity to any one of SEQ ID NOs 1 to 382 or a genetic variation that disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020, or a compliment thereof.

### Claim 106 (depends on 104)

The isolated polynucleotide sequence or fragment thereof, of claim 104, comprising at least 80% identity to any one of SEQ ID NOs 1 to 382 or a genetic variation that disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020, or a compliment thereof.

### Claim 107 (depends on 104)

The isolated polynucleotide sequence or fragment thereof, of claim 104, comprising at least 90% identity to any one of SEQ ID NOs 1 to 382 or a genetic variation that disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020, or a compliment thereof.

### Claim 108 (depends on 104)

The isolated polynucleotide sequence or fragment thereof, of claim 104, comprising at least 95% identity to any one of SEQ ID NOs 1 to 382 or a genetic variation that disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020, or a compliment thereof.

### Claim at position 45

-114. (canceled)

### Claim 115 (depends on 104)

The isolated polynucleotide sequence, or fragment thereof, of claim 104, wherein the polynucleotide sequence comprises a genetic variation not present in the human genome March 2006 (NCBI36/hg18) assembly.

### Claim 116 (depends on 104)

The isolated polynucleotide sequence fragment of claim 104, wherein the polynucleotide sequence fragment comprises a nucleic acid probe, wherein the nucleic acid primer is capable of hybridization to a nucleic acid of interest and initiation of extension or amplifying the nucleic acid of interest.

### Claim at position 48

-119. (canceled)

### Claim 120

A cDNA encoded by an RNA sequence transcribed from any one of SEQ ID NOs 383 to 1020.

### Claim 121

A host cell comprising an expression control sequence operably linked to a polynucleotide sequence selected from the group consisting of a polynucleotide sequence encoded by any one of SEQ ID NOs 383 to 1020, or a fragment thereof.

### Claim 122 (depends on 120)

The cDNA of claim 120, wherein the cDNA comprises a genetic variation not present in the human genome March 2006 (NCBI36/hgl 8) assembly.

### Claim at position 52

-127. (canceled)

### Claim 128

A panel of biomarkers for detection of an ND comprising two or more fragments of (a) one or more polynucleotide sequences selected from SEQ ID NOs 1 to 382, or (b) one or more polynucleotide sequences containing a genetic variation that disrupts or modulates a genomic sequence encoded by any one of SEQ ID NOs 383 to 1020.

### Claim 129

(canceled)

### Claim 130 (depends on 128)

The panel of claim 128, wherein the panel comprises fragments of at least 5, 10, 25, 50, 100, or 200 polynucleotide sequences selected from SEQ ID NOs 383 to 1020.

### Claim 131

(canceled)

### Claim 132

(canceled)

### Claim 133 (depends on 128)

The panel of claim 128, wherein the fragments are arrayed on a flat substrate, attached to one or more beads, or attached to a solid support.

### Claim at position 59

-139. (canceled)

### Claim 140 (depends on 128)

The panel of claim 128, wherein the panel is an in silico panel.

### Claim 141

A method for measuring expression levels of polynucleotide sequences from biomarkers for an ND in a subject, comprising:
a) selecting a panel of biomarkers comprising two or more genes contained in one or more polynucleotide sequences selected from SEQ ID NOs 383 to 1020;
b) isolating cellular RNA from a nucleic acid sample obtained from the subject;
c) synthesizing cDNA from the cellular RNA for each biomarker in the panel using suitable primers;
d) optionally amplifying the cDNA; and
e) quantifying levels of the cDNA from the nucleic acid sample.

### Claim at position 62

-148. (canceled)

### Claim 149

A method for measuring expression levels of polypeptides from biomarkers for an ND in a subject comprising:
a) selecting a panel of biomarkers comprising at least two polypeptides encoded by an RNA sequence transcribed from a genomic sequence of SEQ ID NOs 383 to 1020;
b) obtaining a polypeptide sample from the subject;
c) creating an antibody/aptamer panel for each biomarker in the panel;
d) using the antibody/aptamer panel to bind the polypeptides from the polypeptide sample; and
e) quantifying levels of the polypeptides bound from the polypeptide sample to the antibody/aptamer panel.

### Claim at position 64

-199. (canceled)