Loss of LDAH associated with prostate cancer and hearing loss.

Currall, Benjamin B

Chen, Ming

Sallari, Richard C

Cotter, Maura

Wong, Kristen E

Robertson, Nahid G

Penney, Kathryn L

Lunardi, Andrea

Reschke, Markus

Hickox, Ann E

Yin, Yanbo

Wong, Garrett T

Fung, Jacqueline

Brown, Kerry K

Williamson, Robin E

Sinnott-Armstrong, Nicholas A

Kammin, Tammy

Ivanov, Andrew

Zepeda-Mendoza, Cinthya J

Shen, Jun

Quade, Bradley J

Signoretti, Sabina

Arnos, Kathleen S

Banks, Alexander S

Patsopoulos, Nikolaos

Liberman, M Charles

Kellis, Manolis

Pandolfi, Pier Paolo

Morton, Cynthia C

2020-04-06T05:39:17Z

2020-04-06T05:39:17Z

2018-12

2020-04-06T05:39:04Z

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.

5087742

0964-6906

1460-2083

https://hdl.handle.net/10161/20376

eng

Oxford University Press (OUP)

Human molecular genetics

10.1093/hmg/ddy310

Germ Cells

Animals

Mice, Knockout

Humans

Mice

Prostatic Neoplasms

Hearing Loss, Sensorineural

Translocation, Genetic

Phenotype

Adult

Aged

Male

Genome-Wide Association Study

Serine Proteases

Loss of LDAH associated with prostate cancer and hearing loss.

Journal article

Chen, Ming|0000-0002-3470-1062

4194

4203

24

School of Medicine

Duke Cancer Institute

Pathology

Duke

Institutes and Centers

Clinical Science Departments

Published

27