Detection of the de novo Pro253Arg Mutation of Fibroblast Growth Factor Receptor 2 (FGFR2) in a Pediatric Patient with Congenital Hand Anomaly
Main Article Content
Abstract
Congenital hand deformities are a group of birth defects related to abnormal development of soft, cartilage, or bone tissues in the hands. Recent studies have indicated that the most usual reason of congenital hand anomalies are due to the genetic factors. In this study, we sequenced the exome of a 2.5-year-old female patient case with bilateral hand deformity. Results revealed that the patient did not carry mutations in the expression region of the GLI3 and SHH genes. However, the patient did have a heterozygous mutation: FGFR2: c.C758G, p.P253R. Sanger sequencing confirmed this was a de novo mutation as it was not detected in her parents. In silico analyses indicated that P253R has a potential effect to alter the structure and function of the fibroblast growth factor receptor, consequently disrupting the processes involved in the formation and development of bone and cartilage tissues. Overall, this research will contribute to a better understanding of the role and functionality of the FGF molecular signaling network in the development and synthesis of bone and cartilage tissues, particularly during the embryonic stage.
Keywords:
Syndactyly, FGFR2, Exome sequencing, Congenital hand anomaly, Case-study.
References
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[4] J. A. Fearon, Treatment of the Hands and Feet in Apert Syndrome: An Evolution in Management, Plastic and Reconstructive Surgery, 2003, Vol. 112, No. 1, 2003, pp. 1-12, https://doi.org/10.1097/01.PRS.0000065908.60382.17.
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https://doi.org/10.3390/ijms22189854.
[7] N. T. Ngoc, N. T. Duong, D. H. Quynh, N. D. Ton, H. H. Duc, L. T. M. Huong, L. T. L. Anh,
N. V. Hai, Identification of Novel Missense Mutations Associated with Non-Syndromic Syndactyly in Two Vietnamese Trios by Whole Exome Sequencing, Clinica Chimica Acta, Vol. 506, 2020, pp. 16-21, https://doi.org/ 10.1016/j.cca.2020.03.017.
[8] S. J. Matissek, S. F. Elsawa, GLI3: A Mediator of Genetic Diseases, Development and Cancer, Cell Communication and Signaling, 2020, Vol. 18, No. 1, 2020, pp. 54, https://doi.org/10.1186/s12964-020-00540-x.
[9] S. C. Azoury, S. Reddy, V. Shukla, C. X. Deng, Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis, International Journal of Biological Sciences, Vol. 13, No. 12, 2017, pp. 1479-1488,
https://doi.org/ 10.7150/ijbs.22373.
[10] D. Johnson, A. O. Wilkie, Craniosynostosis, European Journal of Human Genetics, Vol. 19, No. 4, 2021, pp. 369-376, https://doi.org/ 10.1038/ejhg.2010.235.
[11] L. Chen, C. X. Deng, Roles of FGF Signaling in Skeletal Development and Human Genetic Diseases, Frontiers in Bioscience: A journal and Virtual Library, Vol. 10, 2005, pp. 1961-1976, https://doi.org/10.2741/1671.
[12] M. F. Hoefkens, C. V. Keers, J. M. Vaandrager, Crouzon Syndrome: Phenotypic Signs and Symptoms of the Postnatally Expressed Subtype, The Journal of Craniofacial Surgery, Vol. 15, No. 2, 2004, pp. 233-240,
https://doi.org/10.1097/00001665-200403000-00013.
[13] H. Li, R. Durbin, Fast and Accurate Short Read Alignment with Burrows-Wheeler Transform, Bioinformatics, Vol. 25, No. 14, 2009, pp. 1754-1760, https://doi.org/10.1093/bioinformatics/btp324.
[14] G. A. V. D. Auwera, M. O. Carneiro, C. Hartl, R. Poplin, G. Del Angel, A. L. Moonshine, T. Jordan, K. Shakir, D. Roazen, J. Thibault, From FastQ Data to High Confidence Variant Calls: the Genome Analysis Toolkit Best Practices Pipeline, Current Protocols in Bioinformatics, Vol. 43, No. 1110, 2013, pp. 11-33, https://doi.org/10.1002/0471250953.bi1110s43.
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https://doi.org/10.1371/journal.pcbi.1004962.
[17] C. M. Teven, E. M. Farina, J. Rivas, R. R. Reid, Fibroblast Growth Factor (FGF) Signaling in Development and Skeletal Diseases, Genes and Diseases, Vol. 1, No. 2, 2014, pp. 199-213,
https://doi.org/ 10.1016/j.gendis.2014.09.005.
[18] N. Turner, R. Grose, Fibroblast Growth Factor Signalling: from Development to Cancer, Nature Reviews Cancer, No. 10, Vol. 2, 2010, pp.116-129, https://doi.org/10.1038/nrc2780.
[19] M. Tekin, B. O. Hismi, S. Fitoz, H. Ozdag, F. B. Cengiz, A. Sirmaci, I. Aslan, B. Inceoglu, E. B. Y. Konuk, S. T. Yilmaz et al., Homozygous Mutations in Fibroblast Growth Factor 3 are Associated with a New form of Syndromic Deafness Characterized by Inner Ear Agenesis, Microtia, and Microdontia, American Journal of Human Genetics, Vol. 80, No. 2, 2007, pp. 338-344, https://doi.org/10.1086/510920.
[20] S. H. Kan, N. Elanko, D. Johnson, L. C. Roldan, J. Cook, E. W. Reich, S. Tomkins, A. Verloes,
S. R. Twigg, S. R. Eliya et al., Genomic Screening of Fibroblast Growth-Factor Receptor 2 Reveals a Wide Spectrum of Mutations in Patients with Syndromic Craniosynostosis, American Journal of Human Genetics, Vol. 70, No. 2, 2002, pp. 472-486, https://doi.org/10.1086/338758.
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https://doi.org/10.1002/10.1016/j.genrep.2020.100995.
[22] C. B. Singh, B. Mishra, R. Patel, A. Kumar, A. Ali, Tripod-Shaped Syndactyly in Apert Syndrome with FGFR2.P253R Mutation, Indian Journal of Plastic Surgery, Vol. 54, No. 3, 2021, pp. 370-372, https://doi.org/10.1055/s-0041-1733808.
[23] L. Yin, X. D, C. Li, X. Xu, Z. Chen, N. Su, L. Zhao, H. Qi, F. Li, J. Xue, A Pro253Arg Mutation in Fibroblast Growth Factor Receptor 2 (Fgfr2) Causes Skeleton Malformation Mimicking Human Apert Syndrome by Affecting Both Chondrogenesis and Osteogenesis, Bone, Vol. 42, No. 4, 2008, pp. 631-643, https://doi.org/10.1016/j.bone.2007.11.019.