DGAP

The Developmental Genome Anatomy Project (DGAP) was developed by my mentor Cynthia C. Morton, Ph.D. The goal of the project is to understand the genetic etiology of diseases using chromosomal rearrangements as a sign post. This approach has been successful in identifying nearly 200 genes involved in congenital abnormalities covering disease such as autism, cranial-facial dysmorphias and hearing loss.

I have led the research on several DGAP subjects, most involving a hearing loss phenotype. Like many genetic studies, these individuals have led us to discovering much more about the complexity and beauty of genetics than is originally expected. Listed here are the cases that are of particular interest to me:

DGAP056

Several recent GWAS and linkage studies have associated the SNP, rs13385191, with prostate cancer (PCa). Moreover, this SNP is suggested to be a cis-acting expressed quantitative locus (eQTL), which down-regulates the expression of a poorly annotated gene known as C2orf43. These data parallel findings in a human subject, enrolled in the Developmental Genome Anatomy Project (DGAP, www.dgap.harvard.edu) and referred to as DGAP056, who has a chromosomal translocation that disrupts C2orf43, resulting in decreased expression of this gene, and who developed early-onset PCa (age 38). Analysis of RNA expression in human primary and metastatic tumors, from the Memorial Sloan Kettering Cancer Center (MSKCC) prostate repository, shows that C2orf43 is one of the most frequently down-regulated genes in PCa and is even further reduced in metastatic prostate tumors as compared to primary prostate tumors. Importantly, C2orf43 knockout (KO) mice show both more severe and an increased rate (>3-fold) of prostate tumors than their wild-type (WT) littermates, substantiating that C2orf43 down-regulation is causative for prostate tumorigenesis. Accompanied with recent findings that C2orf43 is involved in intracellular cholesterol ester (iCE) metabolism and that elevated iCE is a common finding in PCa, these convergent data suggest that C2orf43 is central to a relatively unknown PCa pathway.

 

DGAP120

DGAP120 is a subject with “cookie bite” hearing loss, NGS identified disruption of a novel gene, known as ADGB, which has no known function.

 

DGAP137

In a complex case that included both hearing loss and café-au-lait spots, karyotyping, array comparative genomic hybridization (aCGH) and NGS were combined to identify the loss of KIT, an established hearing loss gene

 

DGAP242

In DGAP242, a subject with non-syndromic high frequency hearing loss, NGS revealed disruption of ESRRG, a gene that has only recently been associated with hearing loss through genome-wide association studies (GWAS).