Clinical experience of the expanded carrier screening for recessive genetic diseases in a large cohort study in Southern central China

Abstract

Recessive monogenic disorders represent a significant cause of congenital malformations and disabilities in pediatric populations. The present study aims to provide the first comprehensive assessment of clinical experience with expanded carrier screening (ECS) panels in a large cohort from the Jiangxi province of Southern Central China. An ECS panel encompassing 147 genes associated with 155 genetic disorders was initially performed on 5,104 pre-gestational/prenatal females using next-generation sequencing. Following the identification of autosomal recessive conditions in female partners, sequential genetic testing was offered to 1,351 male partners, which included either the same ECS panel or other appropriate genetic tests. Comprehensive reproductive counseling was provided to all the identified at-risk couples (ARCs). Overall, 6,308 participants accepted ECS for 155 conditions (Female: 5,104, Male: 1,204) and approximately 38.43% (2,424/6,308) of them were detected as carriers for at least one of the 155 genetic conditions. The top four prevalent conditions identified in Jiangxi Province were α-thalassemia, GJB2-associated hearing loss, Krabbe disease and Wilson's disease. Among the participated cohort, 1,960 females were identified with AR variants and 1,351 male partners received sequential testing, at a recall rate of 68.93%. Among the tested couples, a total of 36 ARCs (36/1,357, 2.65%) were identified with the same AR (n = 27) or X-linked conditions (n = 9). Our study represents the first large-scale demonstration of the substantial feasibility of ECS in the Jiangxi population of Southern Central China. Based on our findings, we propose that incorporating genes with a carrier frequency threshold of 1/2,000 in the screening panel could serve as an optimal criterion. Our findings may contribute significantly to facilitating future clinical implementations of ECS.

Keywords: Expanded carrier screening; Recessive conditions, at-risk couples; Southern Central China.

Fig. 1

Information on the different disease systems involved in the ECS panel. IED: immune and endocrine disorders; DUD: digestive and urinary disorder; MSD: multi-system disorder; NMD: neurological and musculoskeletal disorder; SD: skin disorder; RHD: Respiratory and hearing disorder; BD: blood disorder; IMD: inherited metabolic disorder.

Fig. 2

The overall results of ECS and the ARCs. The number of subjects was indicated in brackets. AR: autosomal recessive; XL: X-linked.

Fig. 3

The overall clinical performance of CCR and ACR of the ECS panel in our study. Cumulative carrier rates (CCR) and at-risk couple rate (ACR) across varying numbers of screened genes. (a) The CCR and number of genes in different GCR cutoffs. (b) ACR for the varying number of selected AR genes. Genes are ranked in descending order based on gene carrier rate (GCR) among the 6,308 individuals in our cohort.