Loss of LDAH associated with prostate cancer and hearing loss.
Publication/Presentation Date
12-15-2018
Abstract
Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the underpinnings of a constellation of phenotypes that include prostate cancer (PCa) and sensorineural hearing loss (SNHL) in a human subject. Through interrogation of the subject's de novo, germline, balanced chromosomal translocation, we first identify a correlation between his disorders and a poorly annotated gene known as lipid droplet associated hydrolase (LDAH). Using data repositories of both germline and somatic variants, we identify convergent genomic evidence that substantiates a correlation between loss of LDAH and PCa. This correlation is validated through both in vitro and in vivo models that show loss of LDAH results in increased risk of PCa and, to a lesser extent, SNHL. By leveraging convergent evidence in emerging genomic data, we hypothesize that loss of LDAH is involved in PCa and other phenotypes observed in support of a genotype-phenotype association in an n-of-one human subject.
Volume
27
Issue
24
First Page
4194
Last Page
4203
ISSN
1460-2083
Published In/Presented At
Currall, B. B., Chen, M., Sallari, R. C., Cotter, M., Wong, K. E., Robertson, N. G., Penney, K. L., Lunardi, A., Reschke, M., Hickox, A. E., Yin, Y., Wong, G. T., Fung, J., Brown, K. K., Williamson, R. E., Sinnott-Armstrong, N. A., Kammin, T., Ivanov, A., Zepeda-Mendoza, C. J., Shen, J., … Morton, C. C. (2018). Loss of LDAH associated with prostate cancer and hearing loss. Human molecular genetics, 27(24), 4194–4203. https://doi.org/10.1093/hmg/ddy310
Disciplines
Medicine and Health Sciences
PubMedID
30169630
Department(s)
Department of Pathology and Laboratory Medicine
Document Type
Article