Family trios/quartets analysis based on the Newborn Genomic Atlas for Thalassemia project in Guangxi

Thalassemia, a hereditary hemolytic blood disorder, is characterized by high global allele prevalence and a gradually expanding variant spectrum. In Guangxi, China, routine genetic screening targeting hotspot variants of thalassemia has been implemented for over a decade, significantly reducing the incidence of severe cases. This study assessed the efficacy of the existing thalassemia screening protocol in Guangxi, China, by applying long-read sequencing (LRS) in family trios/quartets analysis for newborns.

This study enrolled 1491 families for the family trios/quartets analysis, among which at least one of the parents had undergone routine genetic screening for thalassemia. A total of 1516 newborns from these families were tested using LRS. The efficacy of routine screening was assessed by comparing detection results across generations.

α-thalassemia demonstrated higher prevalence than β-thalassemia among newborns, with --^SEA and HBB c.52A > T as the predominant variants. Among the 1516 newborns, 1348 (88.92%) exhibited LRS results that were concordant with the predictions from parental screening. Of these 1348 newborns, 28 had parents who had undergone routine prenatal diagnosis. Discordance between the predictions from parental screening and newborn test results occurred in 168 cases (11.08%), with 154 (10.16%) of these attributable to genetic testing of only one of the parents or incomplete testing of both parents, while the remaining 14 (0.92%) were attributed to limitations of routine methods in detecting complex structural variants and rare point mutations.

Although routine genetic screening targeting hotspot variants is highly effective, its precision is constrained by strategic and methodological limitations. A comprehensive and accurate LRS-based screening method can serve as a valuable supplement to routine screening, enhancing the precision of thalassemia prevention and management.