How effective is universal carrier screening to encompass turkish population mutation profile?

According to WHO, 8000 people (in every 100000) are affected with rare diseases and in Turkey 6-8 million people are affected by rare diseases. There are around 8000 rare diseases known in the world and an average of 5 new diseases are described every week. Since the vast majority of genetic diseases cannot be cured, it is of great importance to identify carrier status of partners and prevent affected child births with prenatal or preimplantation genetic methods. Consanguineous marriages have been a major health burden in our country highlighting crucial need of eradication of single gene disorders. In this study, we investigated the adequacy of carrier panels screening 200-600 different conditions. Our approach was to investigate all pathogenic and likely pathogenic variants in 200 whole exom sequencing (WES) cases without considering the clinical phenotype and combine this data with variant list of all PGT-M cases to obtain rare mutaion profile of Turkish population. We compared gene overlap for 2 different commercially available carrier screening tests encompassing 201 and 647 genes and WES mutation results in 301 genes for 200 patients. WES was performed using Twist Human Core Exome Plus kit. Data were analysed using Ingenuity Variant Analysis software according to ACMG guidelines. Variants were filtered according to QC scores (read depth, allel fraction, call quailty), minor allele frequency (%1> in all major databases) and pathogenicity status (in HGMD, Clinvar or predicted pathogenic/likely pathogenic). Additionally, we have included 264 genes from PGT-M data. 26 out of 965 genes (2.7%) were present in all 4 groups. 360 genes were solely observed in Panel 1, while this number was 13 in Panel 2, 176 for WES and 124 for PGT-M. 304 genes observed in WES and PGT-M cases were not covered by both panels. WES reveals that the variant frequency of the most common genes (top 15 genes) constitute only 34% of all variants detected. Carrier screening is an essential public health requirement, especially in countries where high consanguineous marriage is observed. Since commercially available panethnic panels do not fully meet the needs of geographical regions, no panel can be designated as universal. This hypothesis is supported by the comparison results revealing that 360 genes in Panel 1 do not overlap with any other group. The most important reason for this is high consanguinity in our country underlying rare genetic variants and it is noteworthy that 65% of the families applying for PGT-M are carriers of rare diseases. This is also highlighted in the outcome of the study, where variant frequency of the most common genes (top 15 genes) in WES cases constitutes only 34% of all variants detected. Furthermore, since mutation databases are not well-established in our population, especially in rare diseases, variants of uncertain significance (VUS) are frequently encountered. Therefore, these kind of studies constitute an important source of information for the creation of community-specific panels.