Systems and methods for identifying sequence variation associated with genetic diseases

Abstract

Systems and method for identifying variants associated with a genetic disease can include obtaining sequencing reads for a plurality of individuals for a list of variant positions. The reads can be compared to identify variants that are found in affected individuals and absent in non-affected individuals. Such variants can include loss of heterozygosity, trans-phased compound heterozygotes, increased frequency mitochondrial variants, homozygous recessive variants, de novo variants, sex-linked variants, and combinations thereof.

What is claimed is: 
     
         1 . A method for identify variants associated with a genetic disease or trait, comprising:
 mapping a plurality of sequencing reads from a plurality of subjects to a reference genome, the subjects including affected individuals that are affected by a genetic disease or trait and unaffected individuals that are not affected by the genetic disease or trait;   identifying differences between the plurality of sequencing reads from the subjects and the reference genome;   performing a quality check to validate a defined biological relationship between the subjects;   comparing the presence or absence of genetic variants in the subjects;   using a processor to identify patterns of variants found in the affected individuals and not in the unaffected individuals; and   outputting the identified patterns of variants.   
     
     
         2 . The method of  claim 1 , wherein the patterns of variants include loss of heterozygosity, trans-phased compound heterozygotes, increased frequency mitochondrial variants, or combinations thereof. 
     
     
         3 . The method of  claim 2 , wherein the patterns of variants further include recessive variants, de novo variants, sex-linked variants, or combinations thereof. 
     
     
         4 . The method of  claim 1 , wherein the plurality of subjects include a first biological relative, a second biological relative, and a proband. 
     
     
         5 . The method of  claim 4 , wherein the plurality of subjects further includes an unaffected offspring. 
     
     
         6 . The method of  claim 4 , further comprising identifying, based on the patterns of variants, an allele inconsistency that shows inconsistent allele inheritance from the first biological relative and the second biological relative. 
     
     
         7 . The method of  claim 1 , further comprising annotating the variants with functional annotations. 
     
     
         8 . The method of  claim 1 , further comprising:
 joining a first adapter having a first barcode sequence to a first set of polynucleotides from a first subject of the plurality of subjects;   joining a second adapter having a second barcode sequence to a second set of polynucleotides from a second subject of the plurality of subjects;   sequencing the first and second sets of polynucleotides; and   distinguishing between the first and second sets of polynucleotides based on the sequence differences between the first and second barcode sequences.