Methods for determining carrier status

Abstract

The invention generally relates to methods for determining carrier status with respect to a condition or disease. In certain embodiments, the method involves exposing a sample to a plurality of molecular inversion probes capable of capturing DNA from at least one genomic region suspected of having an altered copy number and at least one internal control DNA known or suspected to have a stable copy number, capturing and sequencing DNA that binds to the molecular inversion probes, and determining a copy number state of the at least one genomic region based on the sequence results.

1 . A method for determining copy number state of a gene, the method comprising:
 exposing a plurality of molecular inversion probes to target DNA from a genomic region suspected of having an altered copy number and control DNA having a stable copy number;   capturing DNA that binds the molecular inversion probes;   sequencing the captured DNA to produce target sequence reads and control sequence reads;   obtaining target read counts from the target sequence reads and control read counts from the control sequence reads;   normalizing the target read counts with respect to the control read counts to obtain normalized target read counts and obtaining normalized control read counts; and   determining a copy number state for the genomic region by comparing the normalized target read counts to the normalized control read counts.   
     
     
         2 . The method of  claim 1 , wherein the determining step comprises determining differences between the normalized target read counts and the normalized control read counts based upon the comparison. 
     
     
         3 . The method of  claim 1 , wherein the normalized target read counts and the normalized control read counts are obtained from a first sample. 
     
     
         4 . The method of  claim 1 , wherein the normalized target read counts are obtained from a first sample and the normalized control read counts are obtained from a second sample that is different from the first sample. 
     
     
         5 . The method of  claim 4 , wherein the normalized control read counts are obtained in silico. 
     
     
         6 . The method of  claim 4 , wherein the normalized control read counts are obtained from a synthetic nucleic acid. 
     
     
         7 . The method of  claim 1 , wherein the genomic region comprises a first gene and a second gene, wherein the first and second genes are homologs, orthologs, or paralogs. 
     
     
         8 . The method of  claim 7 , wherein the first gene is SMN1 and the second gene is SMN2. 
     
     
         9 . The method of  claim 8 , further comprising the step of diagnosing a carrier phenotype for spinal muscular atrophy. 
     
     
         10 . The method of  claim 1 , wherein the control read counts are determined empirically. 
     
     
         11 . The method of  claim 1 , wherein the sequencing step comprises a Sanger sequencing method or a next-generation sequencing method. 
     
     
         12 . The method of  claim 1 , wherein the determining step comprises determining a difference between the copy number state of the genomic region to a copy number distribution encompassing a plurality of stable control loci. 
     
     
         13 . The method of  claim 3 , wherein the first sample is selected from blood and tissue.