Filtering for Compound Heterozygous Sequence Variants in Non-Consanguineous Pedigrees

Abstract

The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We developed a web-based compound heterozygous filter that is suited for data from NGS projects and that is easy to use for non-bioinformaticians. We analyzed the power of compound heterozygous mutation filtering by deriving background distributions for healthy individuals from different ethnicities and studied the effectiveness in trios as well as more complex pedigree structures. While usually more then 30 genes harbor potential compound heterozygotes in single exomes, this number can be markedly reduced with every additional member of the pedigree that is included in the analysis. In a real data set with exomes of four family members, two sisters affected by Mabry syndrome and their healthy parents, the disease-causing gene PIGO, which harbors the pathogenic compound heterozygous variants, could be readily identified. Compound heterozygous filtering is an efficient means to reduce the number of candidate mutations in studies aiming at identifying recessive disease genes in non-consanguineous families. A web-server is provided to make this filtering strategy available at www.gene-talk.de.

Haplotype-resolved whole-genome sequencing by contiguity-preserving transposition and combinatorial indexing

“…al. 28 . From a total of 10 pairs and one trio (23 total SNPs), 19 of them are phased by CPT-seq, covering 6 pairs and the trio.…”

Genetic linkage analysis in the age of whole-genome sequencing

“…Linkage analysis can be used to obtain LOD scores for the variants within the region (or regions) of homozygosity through multipoint analysis (for SNP genotyping array data) or two-point linkage (for WGS data). It should be noted that in the very rare circumstance that the disease trait in a consanguineous pedigree is due to compound heterozygous variants 67 , homozygosity mapping will not lead to detection of the region harbouring the causal variants, although linkage analysis results will not be influenced by the variants being compound heterozygotes instead of being homozygous.…”

DOMINO: Using Machine Learning to Predict Genes Associated with Dominant Disorders

“…1,2 In recessive conditions, two of such variants have forcibly to be present in the same gene to cause disease, lowering the number of candidate genes associated with the pathology to only 5-10, genome-wide. 1,3,4 In contrast, any gene harboring one of these 400 variants in a heterozygous state represents potentially a gene associated with a dominant disorder, making it difficult to identify the cause of this class of genetic conditions ( Figure 1A). As a consequence, NGS-based studies appear to be almost 10-fold more efficient in detecting genes associated to recessive disorders as compared to dominant ones.…”