B3993 - Use of a polygenic risk score to stratify for treatment for extreme short stature - 17/02/2022

B number: 
Principal applicant name: 
Brent Richards | Five Prime Sciences Incorporated (Canada)
Dr. Vince Forgetta, Dr. Jasmine Chong, Thomas Harrison, Dr. Yossi Farjoun
Title of project: 
Use of a polygenic risk score to stratify for treatment for extreme short stature
Proposal summary: 

Children with idiopathic short stature (ISS) are defined by height below 2 standard deviations (SD) of the mean for age and sex without any endocrine, metabolic or other disease explaining the short stature. Recently the US Food and Drug Administration has approved Vosoritide for individuals with extreme short stature which is caused by a single gene mutation.

However, there are causes of extreme short stature that are not due a single gene mutation. These include polygenic predisposition to disease. We have recently generated a polygenic risk score that can reliably predict adult height, and this was tested in the ALSPAC cohort. We hypothesize that children who are extremely short due to a polygenic cause may also benefit from Vosoritide therapy.

Therefore, we posit that a polygenic risk score can help to identify children at extreme short stature. It could also help to predict if Vosoritide therapy could be helpful, by assessing if genetic changes in the biological pathway that is influenced by Vosoritide influences height. Last, we can use this polygenic risk score to better understand if extreme short stature is associated with other diseases and medically-relevant traits.

Impact of research: 
We hope that our research program will help children overcome the negative medical consequences of extreme short stature due to a polygenic cause. We feel that this is promising because Vosoritide therapy is already approved for monogenic causes of extreme short stature.
Date proposal received: 
Monday, 7 February, 2022
Date proposal approved: 
Monday, 14 February, 2022
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Bone disorders - arthritis, osteoporosis, Congenital abnormalities, Gastrointestinal, Hypertension, Mental health, Obesity, Respiratory - asthma, GWAS, Proteomics, Blood pressure, BMI, Cardiovascular, Genetic epidemiology