O-145 Limitations of designing carrier screening panels based on estimated frequencies. Concordance between recommendations and observed frequencies

Abstract Study question Are recommended carrier screening (CS) panels suitable worldwide or should they be designed taking into account observed carrier frequencies (CF)? Summary answer Limitations of carrier screening panel recommendations based on estimated frequencies could be avoided with a worldwide-database of observed carrier frequencies. What is known already Currently, there is no consensus for specific gene panel for CS, but some scientific societies, based on estimated carrier frequencies, recommend to analyze a narrow panel rather than exome. The American College of Medical Genetics and Genomics (ACMG) recently recommended a 4-tiered system, encouraging to analyze genes in tier 3, genes with less carrier frequency (tier 4) are only recommended to be analyzed on specific cases. Similarly, Sociedad Española de Fertilidad (SEF) recommends in absence of genetic matching (GM) a 6 gene basic panel for donor screening and in a GM context suggests a 50-diseases panel. Study design, size, duration This study includes 8542 patients analyzed with an expanded carrier screening panel of 300 genes, including autosomal recessive (AR) and X-linked (XL) disorders by next-generation sequencing (NGS). ACMG guidelines were followed for variant interpretation and only pathogenic and likely pathogenic variants were reported. The study has been conducted between August 2018 and December 2021. Participants/materials, setting, methods DNA was extracted and sequenced. Obtained data was processed by bioinformatic tools. CF for diseases analyzed was stablished. Genes were categorized according to tier-3 of the ACMG recommendations (112 genes, only 80 included on this study) and also by 50-disease panel of SEF recommendations (49 genes, 40 included on this study). Likewise, analyzed diseases were divided in two groups according to the obtained CF: A (CF ≤ 1/200 - 56 genes); B (CF > 1/200 - 244 genes). Main results and the role of chance The analysis of the 8542 patients showed that 2582 (30.23%) of them were not carriers of any disease analyzed, 2205 (25.81%) of them were only carriers of one or more of the diseases included in the ACMG tier3 panel and 3755 (43.96%) were carriers of at least one disease not included this category. When diseases analyzed were categorized by SEF 50-disease panel, 2280 (26.69%) patients were only carriers of one or more of the diseases included in this panel and 3680 (43.08%) were carriers of at least one disease that would not be analyzed b