Population-based carrier screening and prenatal diagnosis of fragile X syndrome in East Asian populations

Qiwei Guo; Yih-Yuan Chang; Chien-Hao Huang; Yu-Shan Hsiao; Yu-Chiao Hsiao; I-Fan Chiu; Yulin Zhou; Haixia Zhang; Tsang-Ming Ko

doi:10.1016/j.jgg.2021.04.012

Volume 48 Issue 12

Dec. 2021

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2021 > 48(12): 1104-1110

PDF( 545 KB)

Population-based carrier screening and prenatal diagnosis of fragile X syndrome in East Asian populations

doi: 10.1016/j.jgg.2021.04.012

a. United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine & School of Public Health, Xiamen University, Xiamen, Fujian 361102, China;
b. Genephile Bioscience Laboratory, Ko's Obstetrics and Gynecology, Taipei 100, Taiwan, China;
c. Biofast Biotechnology Co., Ltd., Xiamen, Fujian 361102, China

Funds:

We thank all the participants for their kind support of this work. This work supported by the National Natural Science Foundation of China (82071662, to Q.G.).

Received Date: 2021-01-21
Accepted Date: 2021-04-28
Rev Recd Date: 2021-04-13
Publish Date: 2021-12-20

Abstract

Abstract

Identification of carriers of fragile X syndrome (FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39, 458 East Asian adult women and prenatal diagnosis from 87 FXS carriers. The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization; the integral risks of full mutation expansion were approximately 6.0%, 43.8%, and 100% for premutation alleles with 55–74, 75–89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG (adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75–89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXS-associated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.
- AGG interruption,
- East Asian population,
- Fragile X syndrome,
- Population-based carrier screening,
- Prenatal diagnosis,
- Cost-effectiveness analysis

FullText(HTML)

References(39)

References

American College of Obstetricians and Gynecologists' Committee on Genetics, 2017. Committee opinion No. 691: carrier screening for genetic conditions. Obstet. Gynecol. 129, e41-e55.

Archibald, A.D., Smith, M.J., Burgess, T., Scarff, K.L., Elliott, J., Hunt, C.E., McDonald, Z., Barns-Jenkins, C., Holt, C., Sandoval, K., et al., 2018. Reproductive genetic carrier screening for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy in Australia: outcomes of 12, 000 tests. Genet. Med. 20, 513-523.

Biancalana, V., Glaeser, D., McQuaid, S., Steinbach, P., 2015. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur. J. Hum. Genet. 23, 417-425.

Cheng, Y.K., Lin, C.S., Kwok, Y.K., Chan, Y.M., Lau, T.K., Leung, T.Y., Choy, K.W., 2017. Identification of fragile X pre-mutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay: implications for screening and prenatal diagnosis. Hong Kong Med. J. 23, 110-116.

Chevreul, K., Gandre, C., Brigham, K.B., Lopez-Bastida, J., Linertova, R., OlivaMoreno, J., Serrano-Aguilar, P., Posada-de-la-Paz, M., Taruscio, D., Schieppati, A., et al., 2016. Social/economic costs and health-related quality of life in patients with fragile X syndrome in europe. Eur. J. Health Econ. 17 (Suppl. 1), 43-52.

Dean, D.D., Agarwal, S., Muthuswamy, S., 2019. Defining the role of FMR1 gene in unexplained recurrent spontaneous abortion. J. Assist. Reprod. Genet. 36, 2245-2250.

Dimmock, D.P., 2017. Should we implement population screening for fragile X? Genet. Med. 19, 1295-1299.

Dolzhenko, E., van Vugt, J., Shaw, R.J., Bekritsky, M.A., van Blitterswijk, M., Narzisi, G., Ajay, S.S., Rajan, V., Lajoie, B.R., Johnson, N.H., et al., 2017. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 27, 1895-1903.

Domniz, N., Ries-Levavi, L., Cohen, Y., Marom-Haham, L., Berkenstadt, M., Pras, E., Glicksman, A., Tortora, N., Latham, G.J., Hadd, A.G., et al., 2018. Absence of AGG interruptions is a risk factor for full mutation expansion among Israeli FMR1 premutation carriers. Front. Genet. 9, 606.

Gao, F., Huang, W., You, Y., Huang, J., Zhao, J., Xue, J., Kang, H., Zhu, Y., Hu, Z., Allen, E.G., et al., 2020. 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. Mol. Genet. Genomic Med. 8, e1236.

Giesselmann, P., Brandl, B., Raimondeau, E., Bowen, R., Rohrandt, C., Tandon, R., Kretzmer, H., Assum, G., Galonska, C., Siebert, R., et al., 2019. Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing. Nat. Biotechnol. 37, 1478-1481.

Huang, W., Xia, Q., Luo, S., He, H., Zhu, T., Du, Q., Duan, R., 2015. Distribution of fragile X mental retardation 1 CGG repeat and flanking haplotypes in a large Chinese population. Mol. Genet. Genomic Med. 3, 172-181.

Huang, W., Xue, J., Kang, H., Guan, X., Teng, Y., Wu, L., Duan, R., 2019. Prenatal diagnosis for 30 women carrying a FMR1 mutation. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 36, 866-869.

Hung, C.C., Lee, C.N., Wang, Y.C., Chen, C.L., Lin, T.K., Su, Y.N., Lin, M.W., Kang, J., Tai, Y.Y., Hsu, W.W., et al., 2019. Fragile X syndrome carrier screening in pregnant women in ChineseHan population. Sci. Rep. 9, 15456.

Jang, J.H., Lee, K., Cho, E.H., Lee, E.H., Kim, J.W., Ki, C.S., 2014. Frequency of FMR1 premutation carriers and rate of expansion to full mutation in a retrospective diagnostic FMR1 Korean sample. Clin. Genet. 85, 441-445.

Johansen Taber, K., Lim-Harashima, J., Naemi, H., Goldberg, J., 2019. Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines. Mol. Genet. Genomic Med. 7, e1024.

Kim, M.J., Kim, D.J., Kim, S.Y., Yang, J.H., Kim, M.H., Lee, S.W., Jeong, S.O., Park, S.Y., Ryu, H.M., 2013. Fragile X carrier screening in Korean women of reproductive age. J. Med. Screen 20, 15-20.

Li, X.C., Song, M.F., Sun, F., Tian, F.J., Wang, Y.M., Wang, B.Y., Chen, J.H., 2018. Fragile X-related protein 1 (FXR1) regulates cyclooxygenase-2 (COX-2) expression at the maternal-fetal interface. Reprod. Fertil. Dev. 30, 1566-1574.

Limprasert, P., Thanakitgosate, J., Jaruthamsophon, K., Sripo, T., 2016. Unique AGG interruption in the CGG repeats of the FMR1 gene exclusively found in Asians linked to a specific snp haplotype. Genet. Res. Int. 2016, 8319287.

Lozano, R., Azarang, A., Wilaisakditipakorn, T., Hagerman, R.J., 2016. Fragile X syndrome: a review of clinical management. Intractable Rare Dis. Res. 5, 145-157.

Ma, Y., Wei, X., Pan, H., Wang, S., Wang, X., Liu, X., Zou, L., Yang, H., Wang, F., Wang, K., et al., 2019. The prevalence of CGG repeat expansion mutation in FMR1 gene in the northern Chinese women of reproductive age. BMC Med. Genet. 20, 81.

Manor, E., Gonen, R., Sarussi, B., Keidar-Friedman, D., Kumar, J., Tang, H.T., Tassone, F., 2019. The role of AGG interruptions in the FMR1 gene stability: A survey in ethnic groups with low and high rate of consanguinity. Mol. Genet. Genomic Med. 7, e00946.

Metcalfe, S.A., Delatycki, M.B., Cohen, J., Archibald, A.D., Emery, J.D., 2018. Fragile X population carrier screening. Genet. Med. 20, 1091-1092.

Metcalfe, S.A., Martyn, M., Ames, A., Anderson, V., Archibald, A.D., Couns, G.D.G., Carter, R., Cohen, J., Cotter, M., GenCouns, M., et al., 2017. Informed decision making and psychosocial outcomes in pregnant and nonpregnant women offered population fragile X carrier screening. Genet. Med. 19, 1346-1355.

Mila, M., Alvarez-Mora, M.I., Madrigal, I., Rodriguez-Revenga, L., 2018. Fragile X syndrome: An overview and update of the FMR1 gene. Clin. Genet. 93, 197-205.

Monaghan, K.G., Lyon, E., Spector, E.B., 2013. Acmg standards and guidelines for fragile X testing: a revision to the disease-specific supplements to the standards and guidelines for clinical genetics laboratories of the american college of medical genetics and genomics. Genet. Med. 15, 575-586.

Nazareth, T., Li, N., Marynchenko, M., Zhou, Z., Chopra, P., Signorovitch, J., Wu, E., Ahmed, S., Marvel, J., Sasane, R., 2016. Burden of illness among patients with fragile X syndrome (FXS): a Medicaid perspective. Curr. Med. Res. Opin. 32, 405-416.

Nolin, S.L., Glicksman, A., Ersalesi, N., Dobkin, C., Brown, W.T., Cao, R., Blatt, E., Sah, S., Latham, G.J., Hadd, A.G., 2015. Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers. Genet. Med. 17, 358-364.

Nolin, S.L., Glicksman, A., Tortora, N., Allen, E., Macpherson, J., Mila, M., ViannaMorgante, A.M., Sherman, S.L., Dobkin, C., Latham, G.J., et al., 2019. Expansions and contractions of the FMR1 CGG repeat in 5, 508 transmissions of normal, intermediate, and premutation alleles. Am. J. Med. Genet. 179, 1148-1156.

Pieretti, M., Zhang, F.P., Fu, Y.H., Warren, S.T., Oostra, B.A., Caskey, C.T., Nelson, D.L., 1991. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817-822.

Sun, J.H., Zhou, L., Emerson, D.J., Phyo, S.A., Titus, K.R., Gong, W., Gilgenast, T.G., Beagan, J.A., Davidson, B.L., Tassone, F., et al., 2018. Disease-associated short tandem repeats co-localize with chromatin domain boundaries. Cell 175, 224-238.

Tzeng, C.C., Tsai, L.P., Chang, Y.K., Hung, Y.J., Chang, Y.Y., Su, Y.P., Jiang, J.J., Liang, H.M., 2017. A 15-year-long southern blotting analysis of FMR1 to detect female carriers and for prenatal diagnosis of fragile X syndrome in taiwan. Clin. Genet. 92, 217-220.

Verkerk, A.J., Pieretti, M., Sutcliffe, J.S., Fu, Y.H., Kuhl, D.P., Pizzuti, A., Reiner, O., Richards, S., Victoria, M.F., Zhang, F.P., et al., 1991. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905-914.

Weiss, K., Orr-Urtreger, A., Kaplan Ber, I., Naiman, T., Shomrat, R., Bardugu, E., Yaron, Y., Ben-Shachar, S., 2014. Ethnic effect on FMR1 carrier rate and AGG repeat interruptions among Ashkenazi women. Genet. Med. 16, 940-944.

Westemeyer, M., Saucier, J., Wallace, J., Prins, S.A., Shetty, A., Malhotra, M., Demko, Z.P., Eng, C.M., Weckstein, L., Boostanfar, R., et al., 2020. Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach. Genet. Med. 22, 1320-1328.

Yrigollen, C.M., Durbin-Johnson, B., Gane, L., Nelson, D.L., Hagerman, R., Hagerman, P.J., Tassone, F., 2012. AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genet. Med. 14, 729-736.

Zhao, X.N., Usdin, K., 2016. Ups and downs: mechanisms of repeat instability in the Fragile X-related disorders. Genes 7, 70.

Zhao, X.N., Usdin, K., 2018. Timing of expansion of Fragile X premutation alleles during intergenerational transmission in a mouse model of the Fragile X-related disorders. Front. Genet. 9, 314.

Zlotogora, J., Grotto, I., Kaliner, E., Gamzu, R., 2016. The Israeli national population program of genetic carrier screening for reproductive purposes. Genet. Med. 18, 203-206.

Relative Articles

Supplements(0)

Cited By

Proportional views