The utility of molecular genetic techniques in craniosynostosis cases associated with intellectual disability

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Abstract

Molecular genetic testing in craniosynostosis leads to the detection of the mutations in the genes encoding fibroblast growth factor receptors (FGFR), providing information about the etiology of the genetic disorder. Muenke syndrome is produced by p.Pro250Arg mutation in FGFR3 gene with evidence of variable expressivity, representing 8% of the syndromic craniosynostoses.

Here, we present the identification of a p.Pro250Arg pathogenic mutation (c.749C>G) in the FGFR3 gene using Multiplex Ligation-dependent Probes Amplification (MLPA) analysis in conjunction with Sanger sequencing in a patient with craniosynostosis and mild intellectual disability. The MLPA analysis detected a reduced signal of the probe, at the site of the c.749C>G mutation, defined by the presence of one allele of C749>G mutation in the FGFR3 gene, exon 7. Sanger sequencing was performed for confirmation and identified heterozygous p.Pro250Arg pathogenic variant (c.749C>G) in exon 7 of the FGFR3.

In conclusion, we assessed the validity and clinical utility of the combined molecular genetic techniques, MLPA analysis, and Sanger sequencing, for craniosynostosis and intellectual disability, improving not only the diagnostic testing but also the genetic counseling and management of the disorder.

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  • 1. Miller K Twigg S McGowan S Phipps J Fenwick A Johnson D et al. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017 Apr;54(4):260-8. DOI: 10.1136/jmedgenet-2016-104215

  • 2. Negura L Negura A. Sanger sequencing of MMR genes in a one-plate system. Rev Romana Med Lab. 2018 Apr;26(2):153-63. DOI: 10.2478/rrlm-2018-0008

  • 3. Addissie Yarnell C Kruszk P Muenke M. Muenke syndrome. Middle East J Med Genet. 2015 Jan;4:1-6. DOI: 10.1097/01.MXE.0000456629.07295.8e

  • 4. Bellus G Gaudenz K Zackai E Clarke L Szabo J Francomano C et al. Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet. 1996 Oct;14(2):174–6. DOI: 10.1038/ng1096-174

  • 5. Muenke M Gripp K McDonald-McGinn D Gaudenz K Whitaker LA L Bartlett S et al. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet. 1997 Mar;60(3):555–64.

  • 6. Boulet S Rasmussen S Honein M. A population-based study of craniosynostosis in metropolitan Atlanta 1989–2003. AmJ Med Genet. 2008 Apr;146A(8):984–91. DOI: 10.1002/ajmg.a.32208

  • 7. Kruszka P Addissie Y Yarnell C Hadley D Guillen Sacoto M Platte P et al. Muenke syndrome: An international multicenter natural history study. Am J Med Genet A. 2016 Apr;170A(4):918–29. DOI: 10.1002/ajmg.a.37528

  • 8. Heuzé Y Holmes G Peter I Richtsmeier J Jabs E. Closing the Gap: Genetic and Genomic Continuum from Syndromic to Nonsyndromic Craniosynostoses. Curr Genet Med Rep. 2014 Sep;2(3):135-45. DOI: 10.1007/s40142-014-0042-x

  • 9. Yu J Park D Yoon S. A Korean Family with the Muenke Syndrome. J Korean Med Sci. 2010 Jul;25(7):1086-9. DOI: 10.3346/jkms.2010.25.7.1086

  • 10. Yoon A Pham B Dipple K. Genetic Screening in Patients with Craniofacial Malformations. J Pediatr Genet. 2016 Dec;5(4):220-4. DOI: 10.1055/s-0036-1592423

  • 11. Wilkie A Johnson D Wall S. Clinical Genetics of Craniosynostosis. Curr Opin Pediatr. 2017 Dec;29(6):622–8. DOI: 10.1097/MOP.0000000000000542

  • 12. Lee E Le T Zhu Y Elakis G Turner A Venselaar H et al. A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations. Genet Med. 2017. DOI: 10.1038/gim.2017.214

  • 13. Twigg S Wilkie A. A Genetic-Pathophysiological Framework for Craniosynostosis. Am J Hum Genet. 2015 Sep;97(3):359-77. DOI: 10.1016/j.ajhg.2015.07.006

  • 14. Nah H Koyama E Agochukwu N Bart S Muenke M. Phenotype profile of a genetic mouse model for Muenke syndrome. Childs Nerv Syst. 2012 Sep;28(9):1483-93. DOI: 10.1007/s00381-012-1778-9

  • 15. Doherty E Lacbawan F Hadley D Brewer C Zalewski C Kim H et al. Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature. Am J Med Genet A. 2007 Dec;143A(24):3204-15. DOI: 10.1002/ajmg.a.32078

  • 16. Escobar L Hiett A Marnocha A. Significant phenotypic variability of Muenke syndrome in identical twins. Am J Med Genet A. 2009 Jun;149A(6):1273-6. DOI: 10.1002/ajmg.a.32841

  • 17. Solomon B Muenke M. Muenke Syndrome. In Muenke M Kress W Collmann H Solomon B editors. Craniosynostoses: Molecular Genetics Principles of Diagnosis and Treatment. Monogr Hum Genet. Basel: Karger; 2011:89-97. DOI: 10.1159/000318407

  • 18. Hamilton A Tétreault M Dyment D Zou R Kernohan K Geraghty M et al. Concordance between whole-exome sequencing and clinical Sanger sequencing: implications for patient care. Mol Genet Genomic Med. 2016 May;4(5):504-12. DOI: 10.1002/mgg3.223

  • 19. Hehr U. Molecular Genetic Testing of Patients with Craniosynostosis. In Muenke M Kress W Collmann H Solomon B editors. Craniosynostoses: Molecular Genetics Principles of Diagnosis and Treatment. Monogr Hum Genet. Basel: Karger; 2011:177–83. DOI: 10.1159/000318428

  • 20. Phipps J Skirton H. A Qualitative Study to Explore the Views and Attitudes towards Prenatal Testing in Adults Who Have Muenke Syndrome and their Partners. J Genet Couns. 2017 Oct;26(5):1130-42. DOI: 10.1007/s10897-017-0094-7

  • 21. Katsanis S Katsanis N. Molecular genetic testing and the future of clinical genomics. Nat Rev Genet. 2013 Jun;14(6):415-26. DOI: 10.1038/nrg3493

  • 22. Sireteanu A Popescu R Braha E Bujoran C Butnariu L Caba L et al. Detection of chromosomal imbalances using combined MLPA kits in patients with syndromic intellectual disability. Rev Romana Med Lab. 2014 Jun;22(2):157-64. DOI: 10.2478/rrlm-2014-0019

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