Development of Chinese genetic reference panel for Fragile X Syndrome and its application to the screen of 10,000 Chinese pregnant women and women planning pregnancy

Abstract

Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability caused by a CGG repeat expansion in the 5′ untranslated region of the FMR1 gene. When the number of repeats exceeds 200, the gene becomes hypermethylated and is transcriptionally silenced, resulting in FXS. Other allelic forms of the gene that are studied because of their instability or phenotypic consequence include intermediate alleles (45–54 CGG repeats) and premutation alleles (55–200 repeats). Normal alleles are classified as having <45 CGG repeats. Population screening studies have been conducted among American and Australian populations; however, large population‐based studies have not been completed in China. Methods and Results In this work we present FXS screening results from 10,145 women of childbearing age from China. We first created and tested a standard panel that was comprised of normal, intermediate, premutation, and full mutation samples, and we performed the screening after confirming the consistency of genotyping results among laboratories. Conclusion Based on our findings, we have determined the intermediate and premutation carrier prevalence of 1/130 and 1/634, respectively, among Chinese women.

Implementation of fragile X syndrome carrier screening during prenatal diagnosis: A pilot study at a single center

“…Since our study had a much smaller sample size than did the Hung's and the Gao's studies, this may also introduce bias to the observed frequency of PM. In our cohort, the frequency of IM was 1/107, close to that (1/130) observed by Gao and colleagues in Chinese women of childbearing age (Gao et al, 2020 ).…”

“…However, recent data from a large cohort of Chinese pregnant women (n = 20,188) showed that the prevalence of PM allele for FXS was as high as 1 in 777, indicating that reproductive FXS carrier screening in this population might be cost‐effective (Hung et al, 2019 ). The prevalence of PM carrier in our cohort was 1/1071, which is slightly lower than that (1/777) observed in the large cohort aforementioned and that (1/634) recently observed in a cohort consisting of 10,145 Chinese women of childbearing age (Gao et al, 2020 ). This difference may result from the inherent bias of our study design.…”

“…Southern blot analysis was applied when the number of CGG repeats was found more than 55 in PCR sequencing analysis. 5 μg of genomic DNA from blood was digested with EcoR I/Eag I, and hybridized with the digoxigenin‐labeled probe StB12.3 (Cat # 11669940910; Roche) as described elsewhere (Gao et al, 2020 ).…”

“…In China, unlike aenuploidy screening that is routinely carried out at obstetric outpatient, preconceptional or prenatal screening of FXS has not been widely established (Gao et al, 2020 ). Meanwhile, people lack the knowledge of FXS and the voluntary screening rate is low in the country.…”

Population-based Carrier Screening and Prenatal Diagnosis of Fragile X Syndrome in East Asian Populations

“…Therefore, a potential cost of 625,000 USD would be required due to the life-cycle burden of FXS patients. In this context, population-based screening would be more cost-saving than targeted screening for preventing the birth of FXS patients (Tables 7 and 8 According to these studies, which had relatively large sample sizes (over 5000), the prevalence of FXS carriers in the general population is 1/530-1/788 in South Korea and 1/564 in Northern China 18,20,21 , while the prevalence of FXS carriers in a population without a family history of FXS-associated conditions is 1/781-1/846 in South Korea and 1/776 in Taiwan [19][20][21] . Ma et al reported a higher prevalence (1/410) of FXS carriers in reproductive women in Northern China 24 .…”