O-145 Limitations of designing carrier screening panels based on estimated frequencies. Concordance between recommendations and observed frequencies
Authors: Trujillo I , Feliu A , Palahi M , Martin A , Moret R , Cotán D , Sandalinas M 
Published: June 2022

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 &gt; 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 by this panel.  

On the other hand, when diseases were divided by observed carrier frequency, a total of 3476 patients (40.69%) were carriers only of a disease(s) included in A group. With this panel, only 2484 (29.08%) of the 8542 patients would not have been correctly diagnosed. Moreover, the variants undetected would affect less frequent diseases (B group).

It is important to notice that group A has been created regarding the data of a 300 gene panel. If another panel would have been analyzed, the group of genes may have changed, but the data collected highlights the importance of observed CF on panel design.

Limitations, reasons for caution

Not all Tier3 ACMG and 50-disease SEF genes are included due to original panel limitations. Observed CF may vary depending on the population analyzed. NGS panel design does not cover variants in regulatory or deep intronic regions. Pseudogenes can interfere. Not all structural variants can be detected by NGS.

Wider implications of the findings

These data highlight the importance of reviewing the genes included in carrier screening panels by their frequency. Furthermore, it points out the need to have updated databases with observed CF available so an universal panel can be designed or adapted to patient’s needs.

Trial registration number

Not applicable