Loss of LDAH associated with prostate cancer and hearing loss.
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.
|Year of Publication
Hum Mol Genet
2018 12 15
|PubMed Central ID
R01 DC000188 / DC / NIDCD NIH HHS / United States
R01 DC003402 / DC / NIDCD NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
P01 GM061354 / GM / NIGMS NIH HHS / United States
F31 DC005712 / DC / NIDCD NIH HHS / United States
K01 DK093638 / DK / NIDDK NIH HHS / United States
P30 DC005209 / DC / NIDCD NIH HHS / United States
F31 DC007540 / DC / NIDCD NIH HHS / United States
F32 DC012466 / DC / NIDCD NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States