Abstract
Neurofibromatosis type 1 (NF1) is the most common neurogenetic disorder worldwide, and its clinical presentations are highly variable. NF1 is caused by mutations in the NF1 gene, and 50% of NF1 cases are sporadic, which occur in the absence of a family history of the disease and usually result from a new mutation in the germline of a parent. Advanced paternal age may increase the risk for germinal NF1 mutations; however, some dominant conditions, including neurofibromatosis, have shown a lesser association with paternal age, although there are conflicting reports in the literature. We investigated the effects of paternal and maternal age in 241 NF1 patients (121 sporadic and 120 familial cases) who were seen in Hacettepe hospital, a reference center for genetic diseases in Turkey. For statistical analysis, Spearman’s and Chi-square tests were used. In this study, we evaluated paternal and maternal age at birth in sporadic and familial cases of NF1. We also compared the effect of parental age on the appearance and coexistence of various NF1 symptoms. There were no significant statistical differences between paternal age and coexistence of the NF1 symptoms. However, a slightly negative correlation was observed between paternal age and the coexistence of NF1 symptoms in familial cases (p < 0.05). We did not find strong evidence for the effect of parental age on the clinical severity of NF1.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J Roy Stat Soc B Met 57:289–300
Bunin GR, Needle M, Riccardi VM (1997) Paternal age and sporadic neurofibromatosis 1: a case-control study and consideration of the methodologic issues. Genet Epidemiol 14(5):507–516. https://doi.org/10.1002/(SICI)1098-2272(1997)14:5<507::AID-GEPI5>3.0.CO;2-Y
Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB (2003) Parental age and risk of schizophrenia: a case-control study. Arch Gen Psychiatry 60(7):673–678. https://doi.org/10.1001/archpsyc.60.7.673
Cantor RM, Yoon JL, Furr J, Lajonchere CM (2007) Paternal age and autism are associated in a family-based sample. Mol Psychiatry 12(5):419–421. https://doi.org/10.1038/sj.mp.4001966
Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1(1):40–47. https://doi.org/10.1038/35049558
Crow JF (2006) Age and sex effects on human mutation rates: an old problem with new complexities. J Radiat Res 47(Suppl B):B75–B82
Dalman C, Allebeck P (2002) Paternal age and schizophrenia: further support for an association. Am J Psychiatry 159(9):1591–1592. https://doi.org/10.1176/appi.ajp.159.9.1591
DeBella K, Szudek J, Friedman JM (2000) Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children Pediatrics 105:608–614
Detjen AK, Tinschert S, Kaufmann D, Algermissen B, Nurnberg P, Schuelke M (2007) Analysis of mitochondrial DNA in discordant monozygotic twins with neurofibromatosis type 1. Twin Res Hum Genet 10(03):486–495. https://doi.org/10.1375/twin.10.3.486
Diggs-Andrews KA, Brown JA, Gianino SM, Rubin JB, Wozniak DF, Gutmann DH (2014) Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol 75(2):309–316. https://doi.org/10.1002/ana.24093
Dubov T, Toledano-Alhadef H, Bokstein F, Constantini S, Ben-Shachar S (2016) The effect of parental age on the presence of de novo mutations—lessons from neurofibromatosis type I. Mol Genet Genomic Med 4(4):480–486. https://doi.org/10.1002/mgg3.222
Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A (2007) Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 44(2):81–88. https://doi.org/10.1136/jmg.2006.045906
Fisch H, Hyun G, Golden R, Hensle TW, Olsson CA, Liberson GL (2003) The influence of paternal age on down syndrome. J Urol 169(6):2275–2278. https://doi.org/10.1097/01.ju.0000067958.36077.d8
Friedman JM (1981) Genetic disease in the offspring of older fathers. Obstet Gynecol 57(6):745–749
Friedman JM (1999) Epidemiology of neurofibromatosis type 1. Am J Med Genet 89(1):1–6. https://doi.org/10.1002/(SICI)1096-8628(19990326)89:1<1::AID-AJMG3>3.0.CO;2-8
Glaser RL, Jabs EW (2004) Dear old dad. Sci Aging Knowledge Environ 2004:re1
Goriely A, Wilkie AO (2012) Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet 90(2):175–200. https://doi.org/10.1016/j.ajhg.2011.12.017
Ittel ME, Niedergang C, Munoz D, Petek F, Okazaki H, Mandel P (1975) Partial purification and characterization of an acid ribonuclease in beef brain nuclei. J Neurochem 25(2):171–176. https://doi.org/10.1111/j.1471-4159.1975.tb12245.x
Kaplan L, Foster R, Shen Y, Parry DM, McMaster ML, O'Leary MC, Gusella JF (2010) Monozygotic twins discordant for neurofibromatosis 1. Am J Med Genet A 152A:601–606
Klose A, Peters H, Hoffmeyer S, Buske A, Lüder A, Hess D, Lehmann R, Nürnberg P, Tinschert S (1999) Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet 83(1):6–12. https://doi.org/10.1002/(SICI)1096-8628(19990305)83:1<6::AID-AJMG3>3.0.CO;2-E
Lazaro C et al (1996) Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum Genet 98(6):696–699
Liu Q, Zoellner N, Gutmann DH, Johnson KJ (2015) Parental age and neurofibromatosis type 1: a report from the NF1 Patient Registry Initiative. Familial Cancer 14(2):317–324. https://doi.org/10.1007/s10689-014-9774-8
Rasmussen SA, Friedman JM (2000) NF1 gene and neurofibromatosis 1. Am J Epidemiol 151:33–40
Risch N, Reich EW, Wishnick MM, McCarthy JG (1987) Spontaneous mutation and parental age in humans. Am J Hum Genet 41(2):218–248
Shi Q, Martin RH (2000) Aneuploidy in human sperm: a review of the frequency and distribution of aneuploidy, effects of donor age and lifestyle factors. Cytogenet Cell Genet 90(3-4):219–226. https://doi.org/10.1159/000056773
Snajderova M, Riccardi VM, Petrak B, Zemkova D, Zapletalova J, Mardesic T, Petrakova A, Lanska V, Marikova T, Bendova S, Havlovicova M, Kaluzova M (2012) The importance of advanced parental age in the origin of neurofibromatosis type 1. Am J Med Genet A 158A(3):519–523. https://doi.org/10.1002/ajmg.a.34413
Szudek J, Evans DG, Friedman JM (2003) Patterns of associations of clinical features in neurofibromatosis 1 (NF1). Hum Genet 112(3):289–297. https://doi.org/10.1007/s00439-002-0871-7
Theos A, Korf BR, American College of P, American Physiological S (2006) Pathophysiology of neurofibromatosis type 1. Ann Intern Med 144:842–849
Toriello HV, Meck JM, Professional P, Guidelines C (2008) Statement on guidance for genetic counseling in advanced paternal age. Genet Med 10(6):457–460. https://doi.org/10.1097/GIM.0b013e318176fabb
Upadhyaya M, Majounie E, Thompson P, Han S, Consoli C, Krawczak M, Cordeiro I, Cooper D (2003) Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet 112(1):12–17. https://doi.org/10.1007/s00439-002-0840-1
Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL (2009) Neurofibromatosis type 1 revisited. Pediatrics 123(1):124–133. https://doi.org/10.1542/peds.2007-3204
Funding
This study was supported by the Hacettepe University Scientific Research and Development Office (Project No. H.U.BAB. 010 T02 102).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical statement
This study was supported by the Hacettepe University Scientific Research and Development Office (Project No. H.U.BAB. 010 T02 102).
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Sharafi, P., Anlar, B., Ersoy-Evans, S. et al. The effect of parental age on NF1 patients in Turkey. J Community Genet 9, 227–232 (2018). https://doi.org/10.1007/s12687-017-0346-0
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s12687-017-0346-0