Compositions And Methods For Diagnosing Autism Spectrum Disorders

Abstract

The invention generally relates to compositions and methods for diagnosing autism spectrum disorders. In certain embodiments, the invention provides a method for diagnosing presence or increased risk of developing an autism spectrum disorder in a subject.

1 . A method for diagnosing the presence or an increased risk of developing an autism spectrum disorder in a subject, the method comprising:
 obtaining a nucleic acid from a tissue or body fluid sample from a subject;   conducting an assay to identify whether there is a variant sequence, or a plurality of variant sequences, in the subject's nucleic acid;   for each variant detected, determining if the variant is a known variant associated with an autism spectrum disorder or a previously undescribed variant;   if the variant is a previously undescribed variant, determining if the variant is expected to have a deleterious effect on at least one of gene expression and/or protein function; and   diagnosing the presence or an increased risk of developing the autism spectrum disorder based on the variant sequence or the plurality of variant sequences detected.   
     
     
         2 . The method according to  claim 1 , wherein the assay comprises at least one of nucleic acid sequencing, hybrid capture, and epigenetic analysis. 
     
     
         3 . The method of  claim 1 , wherein the nucleic acid in the conducting step comprises a gene, an exon, an intron, a gene regulatory element, an expressed RNA, an siRNA, or an epigenetic element. 
     
     
         4 . The method of  claim 1 , wherein the nucleic acid comprises a sequence selected from a sequence known or suspected to be associated with one or more autism spectrum disorders. 
     
     
         5 . The method according to  claim 4 , wherein the nucleic acid comprises at least a portion of one of the genes in Table 1. 
     
     
         6 . The method of  claim 1 , wherein the nucleic acid is derived from a gene that encodes a protein in the metabotropic glutamate receptor signaling pathway. 
     
     
         7 . The method according to  claim 1 , wherein the nucleic acid comprises at least a portion of a gene for at least one of TSC1, TSC2, MECP2, SHANK3, GRM1, GRM5, ARC, EIF4E, HOMER1, HRAS, MAP2K1, MAP2K2, RAF1, PIK3CA, PIK3R1, FMR1, PTEN, RHEB or UBE3A. 
     
     
         8 . The method according to  claim 1 , wherein the nucleic acid comprises at least a portion of a gene for at least one of TSC1, TSC2, SHANK3, or HOMER1. 
     
     
         9 . The method according to  claim 2 , wherein the sequencing comprises at least one of single-molecule sequencing-by-synthesis or massively parallel sequencing. 
     
     
         10 . The method according to  claim 2 , wherein a plurality of DNA samples are analyzed in a pool to identify samples that show a variation. 
     
     
         11 . The method according to  claim 10 , wherein a plurality of DNA samples are analyzed in a plurality of pools to identify an individual sample that shows the same variation in at least two pools. 
     
     
         12 . The method according to  claim 1 , wherein the autism spectrum disorder comprises at least one of non-syndromic autism, classical autism, Asperger's syndrome, Rett's syndrome, childhood disintegrative disorder, or pervasive developmental disorder not otherwise specified (PDD-NOS). 
     
     
         13 . The method according to  claim 1 , wherein the autism spectrum disorder comprises non-syndromic autism. 
     
     
         14 . The method according to  claim 1 , further comprising diagnosing a the presence of, or an increased risk of developing a genetic syndrome linked to autism, wherein the genetic syndrome comprises a manifesting phenotype. 
     
     
         15 . The method according to  claim 14 , wherein the genetic syndrome comprises at least one of Angelman syndrome, Prader-Willi syndrome, 15q11-q13 duplication, fragile X syndrome, fragile X premutation, deletion of chromosome 2q, XYY syndrome, Smith-Lemli-Opitz syndrome, Apert syndrome, mutations in the ARX gene, De Lange syndrome, Smith-Magenis syndrome, Williams syndrome, Noonan syndrome, Down syndrome, velo-cardio-facial syndrome, myotonic dystrophy, Steinert disease, tuberous sclerosis, Duchenne's disease, Timothy syndrome, 10p terminal deletion, Cowden syndrome, 45,X/46,XY mosaicism, Myhre syndrome, Sotos syndrome, Cohen syndrome, Goldenhar syndrome, Joubert syndrome, Lujan-Fryns syndrome, Moebius syndrome, hypomelanosis of Ito, neurofibromatosis type 1, CHARGE syndrome, or HEADD syndrome. 
     
     
         16 . The method according to  claim 1 , wherein the subject is a child. 
     
     
         17 . The method according to  claim 1 , wherein the subject is a fetus. 
     
     
         18 . The method according to  claim 1 , wherein the body fluid comprise at least one of cerebrospinal fluid, blood, amniotic fluid, maternal blood, and urine. 
     
     
         19 . The method according to  claim 1 , wherein the variant comprises at least one of the variants in Table 2. 
     
     
         20 . The method according to  claim 1 , wherein the variant comprises at least one of the following mutations: HOMER 1 c.195G>T, M65I; HOMER 1 c.290C>T, S97L; HOMER 1 c.425C>T, P142L; GRM5 c.3503T>C, L1168P; MAPK2 c.581-1G>T; HRAS c.383G>A, R128Q; a MECP2 c.1477G>T, E483X. 
     
     
         21 . A method for identifying mutations correlated with the presence or increased risk of developing an autism spectrum disorder, the method comprising:
 identifying a nucleic acid to be evaluated as having a sequence that if mutated may be or is associated with the development of autism;   obtaining a nucleic acid sample from a tissue or body fluid sample from a subject having an autism spectrum disorder; and   conducting an assay to identify whether there is a mutation in the nucleic acid sequence in the subject having autism as compared to the nucleic acid sequence in individuals who do not have an autism spectrum disorder, wherein the presence of the mutation in a subject with an autism spectrum disorder indicates that the mutation may be associated with the development of the autism spectrum disorder.   
     
     
         22 . The method of  claim 21 , wherein the mutation is a variant that has been previously associated with the development of an autism spectrum disorder. 
     
     
         23 . The method of  claim 21 , wherein the mutation is a previously undescribed variant. 
     
     
         24 . The method of  claim 21 , further comprising determining if the mutation is expected to have a deleterious effect on at least one of gene expression and/or protein function. 
     
     
         25 . The method of  claim 21 , wherein the nucleic acid sequence for which the presence or absence of a mutation is evaluated is at least a portion of a gene that encodes a protein in the metabotropic glutamate receptor signaling pathway. 
     
     
         26 . The method of  claim 21 , wherein the autism spectrum disorder is non-syndromic autism. 
     
     
         27 . An isolated nucleic acid comprising a variant sequence from at least one of the following genes, TSC1, TSC2, MECP2, SHANK3, GRM1, GRM5, ARC, EIF4E, HOMER1, HRAS, MAP2K1, MAP2K2, RAF1, PIK3CA, PIK3R1, FMR1, PTEN, RHEB or UBE3A, wherein the sequence comprises a variant that is indicative of an autism spectrum disorder. 
     
     
         28 . The isolated nucleic acid of  claim 27 , comprising a variant sequence as described in Table 2. 
     
     
         29 . The isolated nucleic acid of  claim 27 , comprising at least one of the following variants: HOMER 1 c.195G>T, M651; HOMER 1 c.290C>T, S97L; HOMER 1 c.425C>T, P142L; GRM5 c.3503T>C, L1168P; MAPK2 c.581-1G>T; HRAS c.383G>A, R128Q; a MECP2 c.1477G>T, E483X.