Secondary findings in a large Pakistani cohort tested with whole genome sequencing

ABSTRACT Background Studies in the field of genomic secondary findings (SF) are diverse regarding participants’ characteristics; sequencing methods; versions of the ACMG SF gene list. Aim and methods Based on whole genome sequencing (WGS) and version 3.1 of ACMG SF list (ACMG SF), we studied SF in 863 individuals from Pakistan: 62% males; 80% had consanguineous parents. In addition to the ACMG SF we have generated a list of gene-disease pairs that have a clear epidemiological and medically actionable value (non-ACMG SF) in Pakistan. Results The total rate of SF was 4.6%, with rates of ACMG SF – 2.7% and non-AGMG SF – 1.9%. 75.0% of ACMG SF were related to cardiovascular diseases (CVD); cancer predisposition syndromes accounted for 16.7%. Among non-ACMG SF 18.8% belong to eye diseases, followed by neuromuscular – 12.5%, metabolic – 12.5%, and urinary system diseases – 12.5%; CVD accounted for 6.3%. We found high proportion of biallelic mutations among both ACMG (4.2%) and non-ACMG (50%) SF. Conclusions The frequency of ACMG SF is within the range reported in most studies. High proportion of CVD can be explained by inclusion of additional CVD in the ACMG v3.1 SF list. 1.9% of non-ACMG SF and high proportion of biallelic variants are relevant to epidemiology of Pakistan as a country with high rate of consanguineous marriages. In such countries the ACMG criteria for SF can be expanded, and our list of non-ACMG SF is one example. Our findings may help guide the development of standards of practice in genomic medicine and drive future research.