Prevention of Inherited Genetic Disease using WGS (whole genome sequencing)

“An ounce of prevention is worth a pound of cure”. Carrier screening (including pre-conception screening of couples) has been utilized in specific populations to reduce the incidence of specific disorders. The goal of this project is to explore the feasibility and value of using pre-conception genomic testing (PGT) in couples, to counsel them about the risk of having a child with an autosomal recessive or X-linked genetic disease.

Approach: Here we analyze deidentified genomic data of 100 parental couples (mother and father) and develop an algorithm for defining risk alleles, define the limitations of such a genomic approach, and identify key ethical and moral issues that need to be addressed when counseling couples undergoing whole genomic PGT.

Results: We have developed and refined our scheme for prioritizing variants identified in the parents that might be designated as risk alleles. We included variants with an OMIM disorder description, with CADD score >15; we excluded variants scored as benign or likely-benign in the ClinVar database, variants of unknown significance in 3’-UTR, 5’-UTR, and those with more than 5 hemizygotes or homozygotes in the GNOMAD database. In our first 40 couples, we have identified 12 who we would counsel regarding identified potential risk alleles.

Conclusions: It is feasible to use genomic sequencing technologies to develop a pre-conception genetic test for guiding couples who are contemplating having a child. Counseling of couples should begin before testing, should include a thorough discussion of the limitations of testing, and review reproductive options available to the couple.