Application of next-generation sequencing to screen for pathogenic mutations in 123 unrelated Chinese patients with Marfan syndrome or a related disease
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Marfan syndrome (MFS) is a systemic connective tissue disease principally affecting the ocular, skeletal and cardiovascular systems. This autosomal dominant disorder carries a prevalence of 1:3,000 to 1:5,000. This study aims to define the mutational spectrum of MFS related genes in Chinese patients and to establish genotype-phenotype correlations in MFS. Panel-based targeted next-generation sequencing was used to analyze the FBN1, TGFBR1 and TGFBR2 genes in 123 unrelated Chinese individuals with MFS or a related disease. Genotype-phenotype correlation analyses were performed in mutation-positive patients. The results showed that 97 cases/families (78.9%; 97/123) harbor at least one (likely) pathogenic mutation, most of which were in FBN1; four patients had TGFBR1/2 mutations; and one patient harbored a SMAD3 mutation. Three patients had two FBN1 mutations, and all patients showed classical MFS phenotypes. Patients with a dominant negative-FBN1 mutation had a higher prevalence of ectopia lentis (EL). Patients carrying a haploinsufficiency-FBN1 mutation tended to have aortic dissection without EL. This study extends the spectrum of genetic backgrounds of MFS and enriches our knowledge of genotype-phenotype correlations.
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We thank all patients and their family members who participated in this study. The study was supported by the National Natural Science Foundation of China (81400187 and 81230015), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002), the Beijing Municipal Science and Technology Commission (Z151100003915078) and the Special Research Fund for Central Public Scientific Research Institutes, Peking Union Medical College (2016ZX310160).
- Arnaud, P., Hanna, N., Aubart, M., Leheup, B., Dupuis-Girod, S., Naudion, S., Lacombe, D., Milleron, O., Odent, S., Faivre, L., et al. (2017). Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J Med Genet 54, 100–103.CrossRefGoogle Scholar
- Baetens, M., Van Laer, L., De Leeneer, K., Hellemans, J., De Schrijver, J., Van De Voorde, H., Renard, M., Dietz, H., Lacro, R.V., Menten, B., et al. (2011). Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. Hum Mutat 32, 1053–1062.CrossRefGoogle Scholar
- Faivre, L., Collod-Beroud, G., Callewaert, B., Child, A., Loeys, B.L., Binquet, C., Gautier, E., Arbustini, E., Mayer, K., Arslan-Kirchner, M., et al. (2009). Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Am J Med Genet 149A, 854–860.CrossRefGoogle Scholar
- Franken, R., den Hartog, A.W., Radonic, T., Micha, D., Maugeri, A., van Dijk, F.S., Meijers-Heijboer, H.E., Timmermans, J., Scholte, A.J., van den Berg, M.P., et al. (2015). Beneficial outcome of Losartan therapy depends on type of FBN1 mutation in Marfan syndrome. Circ Cardiovasc Genet 8, 383–388.CrossRefGoogle Scholar
- Franken, R., Teixido-Tura, G., Brion, M., Forteza, A., Rodriguez-Palomares, J., Gutierrez, L., Garcia Dorado, D., Pals, G., Mulder, B. J., and Evangelista, A. (2017). Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome. Heart 103, 1795–1799.CrossRefGoogle Scholar
- Karttunen, L., Raghunath, M., Lonnqvist, L., and Peltonen, L. (1994). A compound-heterozygous Marfan patient: two defective fibrillin alleles result in a lethal phenotype. Am J Hum Genet 55, 1083–1091.Google Scholar
- Mátyás, G., De Paepe, A., Halliday, D., Boileau, C., Pals, G., and Steinmann, B. (2002). Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene. Hum Mutat 19, 443–456.CrossRefGoogle Scholar
- Proost, D., Vandeweyer, G., Meester, J.A.N., Salemink, S., Kempers, M., Ingram, C., Peeters, N., Saenen, J., Vrints, C., Lacro, R.V., et al. (2015). Performant mutation identification using targeted next-generation sequencing of 14 thoracic aortic aneurysm genes. Hum Mutat 36, 808–814.CrossRefGoogle Scholar
- Rommel, K., Karck, M., Haverich, A., Schmidtke, J., and Arslan-Kirchner, M. (2002). Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations. Hum Mutat 20, 406–407.CrossRefGoogle Scholar
- Rommel, K., Karck, M., Haverich, A., von Kodolitsch, Y., Rybczynski, M., Müller, G., Singh, K.K., Schmidtke, J., and Arslan-Kirchner, M. (2005). Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. Hum Mutat 26, 529–539.CrossRefGoogle Scholar
- Sakai, H., Visser, R., Ikegawa, S., Ito, E., Numabe, H., Watanabe, Y., Mikami, H., Kondoh, T., Kitoh, H., Sugiyama, R., et al. (2006). Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. Am J Med Genet 140A, 1719–1725.CrossRefGoogle Scholar