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

Open access


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.

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

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

Journal Information

IMPACT FACTOR 2017: 0.400
5-year IMPACT FACTOR: 0.320

CiteScore 2017: 0.31

SCImago Journal Rank (SJR) 2017: 0.144
Source Normalized Impact per Paper (SNIP) 2017: 0.195


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 42 42 12
PDF Downloads 29 29 8