Familial Exome Sequencing in Rare Pediatric Phenotypes

To discover novel candidate genes associated with rare Mendelian phenotypes, we will conduct individual genomic and phenotypic characterization using genome-wide array, pedigree exome sequencing, candidate genotyping, and pertinent clinical testing to define phenotype. Pedigrees included in this submission will have a variety of clinical pathological phenotypes.]]>
Informed Consent - Living InfantInformed Consent - ParentProbands in these studies will be children who present to Washington University School of Medicine with unique and previously uncharacterized pathological findings with likely Mendelian inheritance. Inclusion criteria consist of parental written informed consent and the ability to provide genomic DNA from the proband(s) and parents, and potentially a healthy sibling who has also provided written informed consent. Exclusion criteria include a lack of written informed consent or the inability to provide genomic DNA. Written informed consent would also permit relevant ancillary clinical studies (e.g. MRI scan, cardiac echocardiography) to be performed either during the proband's clinical course or as part of the characterization of other pedigree members. However, refusal to undergo ancillary testing would not exclude the pedigree from genomic characterization.]]>
This submission will contain various pedigrees with children who present to Washington University School of Medicine/St. Louis Children's Hospital with severe and previously uncharacterized pathological phenotypes with likely Mendelian inheritance. The overarching hypothesis is that these phenotypes are mediated through very rare or private sequence variants which can be identified through exome sequencing. Multiple Washington University researchers may be involved in these projects depending upon the phenotypes observed. Sequencing is performed in either of the University's sequencing facilities, the Genome Technology Access Center or the Genome Institute. Corresponding genotyping is performed by the Washington University Clinical and Molecular Cytogenetics Laboratory. The analysis aligns exome data to the human genome followed by variant calling. The data are then filtered for genes in which parents are heterozygous while the affected offspring are homozygous or compound heterozygotes. If available, identified genes are further filtered against unaffected offspring to remove genes with homozygous or compound heterozygous genotypes which are not relevant to phenotype.]]>