William Crowley, MD
Dr. Crowley and his team have pioneered many novel therapeutic and genetic advances in human reproduction. These include the pioneering of GnRH agonist therapy for children with precocious puberty, a treatment that eventually expanded to treat prostate and breast cancer. He also developed pulsatile GnRH therapy to induce sexual maturation and fertility in men and women who failed to undergo a normal puberty due to Isolated GnRH Deficiency (IGD). His genetic investigations using patients with IGD as a human disease model subsequently has identified many novel genes controlling human reproduction such as the Kisspeptin signaling system. His group continues to use the world’s large cohort (1,600+) of patients with IGD to further elucidate the genetic architecture of human reproduction for the first time. He has also trained >90 biomedical research scientists, 64% of whom are women and >50% are now Full Professors a decade later.
Questions being addressed in the lab
- What is the genetic architecture of the neuroendocrine control of human reproduction? Using 1,600 patients with Isolated GnRH Deficiency that have now been genotyped, whole exome sequenced (WES), and analyzed, his team (and others) have now identified >40 new genes controlling human reproduction.
- What are the determinants of incomplete penetrance in monogenic disorders?
- What are the novel structural defects in the whole exomic sequencing of the IGD cohort that mark novel candidate genes controlling reproduction.
Projects underway to answer these questions
Ongoing detailed Phenotypic and Genotypic Analyses of completed genotyping and WES of ~1,600 patients with well-phenotyped Isolated GnRH Deficiency (IGD)
Functional validation of several candidate rare sequence variants discovered in the IGD cohort using zebrafish modeling using combined morphilino and CASPR/CRISP technologies in collaboration with Drs. Nico Katsanis and Erica Davis of Duke/Northwestern
Determining the role of mendelian vs complex trait genetic contributions to the genes controlling human reproduction in collaboration with Drs. Ben Neale (MGH/Broad) and Cecilia Lindgren (Oxford University and UK Biobank)
Highlighted Publications from the lab
SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome