Acrocephalosyndactylia/diagnostic imaging/genetics; Adult; Base Sequence; Congo; DNA Mutational Analysis; Family Health; Female; Heterozygote; Humans; Infant; Male; Mutation; Radiography; Receptor, Fibroblast Growth Factor, Type 2/genetics; Apert syndrome; Central Africa; Craniosynostosis; Syndactyly; Tandem base substitution
Abstract :
[en] Apert syndrome (OMIM 101200) is a rare genetic condition characterized by craniosynostosis and syndactyly of hands and feet with clinical variability. Two single nucleotides mutations in the linker region between the immunoglobulin-like domains II and IIIa of the ectodomainin the Fibroblast Growth Factor Receptor 2 gene (FGFR2, OMIM 176943) are responsible of the vast majority of cases: c.755C > G; p.Ser252Trp (65%) and c.758C > G; p.Pro253Arg (34%. Three exceptional cases carry multiple substitutions of adjacent nucleotides in the linker region. Here we present a Congolese male patient and his mother, both affected with Apert syndrome of variable severity, carrying a previously undescribed heterozygous mutation of three consecutive nucleotides (c.756_758delGCCinsCTT) in the IgII-IgIIIa linker region. This is the fourth live-born patient to carry a multiple nucleotide substitution in the linker region and is the second alternative amino acid substitutions of the Pro253. Remarkably, this novel mutation was detected in the first Central African patient ever to be tested molecularly for the Apert syndrome. To discriminate between a hitherto unreported mutation and an ethnic specific polymorphism, we tested 105 Congolese controls, and no variation was detected.
Agochukwu, N.B., Solomon, B.D., Benson, L.J., Muenke, M., Talocalcaneal coalition in Muenke syndrome: report of a patient, review of the literature in FGFR-related craniosynostoses, and consideration of mechanism (2013) Am J Med Genet A, 161, pp. 453-460
Averof, M., Rokas, A., Wolfe, K.H., Sharp, P.M., Evidence for a high frequency of simultaneous double-nucleotide substitutions (2000) Sci, 287, pp. 1283-1286
Bazykin, G.A., Kondrashov, F.A., Ogurtsov, A.Y., Sunyaev, S., Kondrashov, A.S., Positive selection at sites of multiple amino acid replacements since rat-mouse divergence (2004) Nat, 429, pp. 558-562
Bochukova, E.G., Roscioli, T., Hedges, D.J., Taylor, I.B., Johnson, D., David, D.J., Rare mutations of FGFR2 causing Apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily (2009) Hum Mutat, 30, pp. 204-211
Breugem, C.C., Fitzpatrick, D.F., Verchere, C., Monozygotic twins with Apert syndrome (2008) Cleft Palate Craniofac J, 45, pp. 101-104
Chen, J.M., Ferec, C., Cooper, D.N., Patterns and mutational signatures of tandem base substitutions causing human inherited disease (2013) Hum Mutat, 34, pp. 1119-1130
Cohen, M.M., Kreiborg, S., Hands and feet in the Apert syndrome (1995) Am J Med Genet, 57, pp. 82-96
Dufton, M.J., Genetic code synonym quotas and amino acid complexity: cutting the cost of proteins? (1997) JTheor Biol, 187, pp. 165-173
Goriely, A., Wilkie, A.O., Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease (2012) Am J Hum Genet, 90, pp. 175-200
Goriely, A., McVean, G.A., Rojmyr, M., Ingemarsson, B., Wilkie, A.O., Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line (2003) Sci, 301, pp. 643-646
Goriely, A., McVean, G.A., van Pelt, A.M., O'Rourke, A.W., Wall, S.A., de Rooij, D.G., Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia (2005) Proc Natl Acad Sci U S A, 102, pp. 6051-6056
Grantham, R., Amino acid difference formula to help explain protein evolution (1974) Sci, 185, pp. 862-864
Ibrahimi, O.A., Eliseenkova, A.V., Plotnikov, A.N., Yu, K., Ornitz, D.M., Mohammadi, M., Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome (2001) Proc Natl Acad Sci U S A, 98, pp. 7182-7187
Kan, S.H., Elanko, N., Johnson, D., Cornejo-Roldan, L., Cook, J., Reich, E.W., Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis (2002) Am J Hum Genet, 70, pp. 472-486
Kondrashov, A.S., Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases (2003) Hum Mutat, 21, pp. 12-27
Lajeunie, E., Cameron, R., El Ghouzzi, V., de Parseval, N., Journeau, P., Gonzales, M., Clinical variability in patients with Apert's syndrome (1999) JNeurosurg, 90, pp. 443-447
Miller, S.A., Dykes, D.D., Polesky, H.F., Asimple salting out procedure for extracting DNA from human nucleated cells (1988) Nucleic Acids Res, 16, p. 1215
Mundhofir, F.E., Sistermans, E.A., Faradz, S.M., Hamel, B.C., P.Ser252Trp and p.Pro253Arg mutations in FGFR2 gene causing Apert syndrome: the first clinical and molecular report of Indonesian patients (2013) Singap Med J, 54, pp. e72-75
Oldridge, M., Lunt, P.W., Zackai, E.H., McDonald-McGinn, D.M., Muenke, M., Moloney, D.M., Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2 (1997) Hum Mol Genet, 6, pp. 137-143
Park, W.J., Theda, C., Maestri, N.E., Meyers, G.A., Fryburg, J.S., Dufresne, C., Analysis of phenotypic features and FGFR2 mutations in Apert syndrome (1995) Am J Hum Genet, 57, pp. 321-328
Risch, N., Reich, E.W., Wishnick, M.M., McCarthy, J.G., Spontaneous mutation and parental age in humans (1987) Am J Hum Genet, 41, pp. 218-248
Sakai, N., Tokunaga, K., Yamazaki, Y., Shida, H., Sakata, Y., Susami, T., Sequence analysis of fibroblast growth factor receptor 2 (FGFR2) in Japanese patients with craniosynostosis (2001) JCraniofac Surg, 12, pp. 580-585
Smith, N.G., Webster, M.T., Ellegren, H., Alow rate of simultaneous double-nucleotide mutations in primates (2003) Mol Biol Evol, 20, pp. 47-53
Whelan, S., Goldman, N., Estimating the frequency of events that cause multiple-nucleotide changes (2004) Genet, 167, pp. 2027-2043
Wilkie, A.O., Slaney, S.F., Oldridge, M., Poole, M.D., Ashworth, G.J., Hockley, A.D., Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome (1995) Nat Genet, 9, pp. 165-172