Journal
HUMAN MOLECULAR GENETICS
Volume 27, Issue 24, Pages 4194-4203Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy310
Keywords
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Funding
- Giovanni Armenise-Harvard Foundation Career Development Award
- [R01 DC003402]
- [P01 GM061354]
- [T32 GM007748]
- [F32 DC012466]
- [F31 DC007540]
- [F31 DC005712]
- [P30 DC005209]
- [R01 DC00188]
- [K01 DK093638]
- [P50 CA092629]
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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.
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