Carrier burden of over 300 diseases in Han Chinese identified by expanded carrier testing of 300 couples using assisted reproductive technology.

Background: Expanded carrier screening (ECS) has become a common practice for identifying carriers of monogenic diseases. However, existing large gene panels are not well-tailored to Chinese populations. In this study, ECS testing for pathogenic variants of both single-nucleotide variants (SNVs) and copy number variants (CNVs) in 330 genes implicated in 342 autosomal recessive (AR) or X-linked diseases was carried out. We assessed the differences in allele frequencies specific to the Chinese population who have used assisted reproductive technology (ART) and the important genes to screen for in this population.

Methodology: A total of 300 heterosexual couples were screened by our ECS panel using next-generation sequencing. A customed bioinformatic algorithm was used to analyze SNVs and CNVs. Guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology were adapted for variant interpretation. Pathogenic or likely pathogenic (P/LP) SNVs located in high homology regions/deletions and duplications of one or more exons in length were independently verified with other methods.

Results: 64.83% of the patients were identified to be carriers of at least one of 342 hereditary conditions. We identified 622 P/LP variants, 4.18% of which were flagged as CNVs. The rate of at-risk couples was 3%. A total of 149 AR diseases accounted for 64.05% of the cumulative carrier rate, and 48 diseases had a carrier rate above 1/200 in the test.

Conclusion: An expanded screening of inherited diseases by incorporating different variant types, especially CNVs, has the potential to reduce the occurrence of severe monogenic diseases in the offspring of patients using ART in China.