Comprehensive analysis of recessive carrier status using exome and genome sequencing data in 1543 Southern Chinese

Abstract

Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern Chinese population is not yet available, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.

Fig. 1. Incremental detection of using ECS panel.

The figure shows the incremental benefits of using an ECS panel. The first tier of carrier screening includes α-thalassaemia and β-thalassaemia with 3.31% of individuals identified as carriers. This is based on Hong Kong’s current antenatal screening guidelines. The second tier includes the pan-ethnic carrier screening disease conditions recommended by ACOG which accumulates spinal muscular atrophy and cystic fibrosis. Using these criteria, 4.73% of individuals were identified as carriers. The third tier is based on the 2017 ACOG guidelines on ECS with a cut-off of 1 in 100. Using these criteria, 35.5% of individuals were identified as carriers. Mutations in GJB2 were the most common, with a carrier rate of 24.5% in the Southern Chinese population (1 in 4 individuals). The fourth tier is a screening cut-off of 1 in 200, 38.7% of individuals were identified as carriers. Within this study, 47.8% of 1543 individuals were carriers of one or more recessive disease conditions.