Neurofibromatosis type 1 causes
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.
Overview
Overview
Neurofibromatosis type 1 can be caused 50% of the time due to an autosomal dominant inherited pattern with the other 50% beign caused due to a de novo mutation on NF1 gene. To review risk factors for the development of neurofibromatosis type 1, click here.
Causes
Causes
- Neurofibromatosis type 1 is a relatively common inherited disorder. The development of this disease is always due to a mutation in the NF1 gene from chromosome 17, which in turn, produces a defective neurofibromin protein.
- 50% of cases of neurofibromatosis type 1 are inherited, with the remainder beign de novo NF1 mutation.[1][2]
De novo mutation
- Neurofibromatosis type 1 due to de novo mutations of NF1, occur in the absence of a family history of the disease, usually from a paternal germline cell mutation.[3][1]
- Multiple de novo pathogenic varients is possible in a same family of individuals with neurofibromatosis type 1.[4][5]
- Causes for NF1 gene mutation are the following:
| Causes for NF1 gene mutation | Percentage |
|---|---|
| Small deletions | 22.4%[6] |
| Non-sense mutations | 17.5%[6] |
| Deletion of several exons | 15.5%[6] |
| Missense mutations | 11.8%[6] |
| Small insertions | 11%[6] |
| Intronic mutations affecting RNA splicing | 10.2%[6] |
| Deletions of the entire NF1 gene | 7.2%[6] |
| Chromosomal anomalies | 1.6%[6] |
| 3-UTR region mutations | 1.6%[6] |
| Large insertions | 1.2%[6] |
- Advanced paternal age increases probability of an NF1 de novo mutation.[1]
- The mutation rate for the NF1 gene, 4.37 (± 0.72) per 100,0000.[7]
Inherited (familial)
- Heterozygous pathogenic variants in NF1 gene are responsible for the developement of neurofibromatosis 1 disease.[8]
- Neurofibromatosis type 1 is inherited in an autosomal dominant fashion.[9][10]
- Inherited neurofibromatosis type 1 has 100% penetrance (no skipping generations).[4][11]
- Unlike many autosomal dominant disorders, where one defective copy of a gene can produce the phenotype, in neurofibromatosis type 1, mutation of two copies are necessary to develope the presentation, this means that many people who inherit only one copy mutation need for a second mutation during lifetime for neurofibromas and other characteristics to arise.[9]
- Due to neurofibromatosis type 1 high prevalence, other concomittant autosomal dominant disorders have been reported, such as Noonan syndrome, multiple endocrine neoplasia type 2, and Huntington disease.[12]
- Neurofibromatosis type 1 mosaicism may also appear and be limited to one segment of the body.[8]
- Parents with mosaicism of neurofibromatosis type 1 have less 50% of chance to transmit the condition to its child, but if transmitted, the mutation will be present in every cell of the newborn, presenting a severe variant.[4]
References
References
- ↑ 1.0 1.1 1.2 Invalid
<ref>tag; no text was provided for refs namedpmid28230061 - ↑ McKeever K, Shepherd CW, Crawford H, Morrison PJ (September 2008). “An epidemiological, clinical and genetic survey of neurofibromatosis type 1 in children under sixteen years of age”. Ulster Med J. 77 (3): 160–3. PMC 2604471. PMID 18956796.
- ↑ 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): 507–16. doi:10.1002/(SICI)1098-2272(1997)14:5<507::AID-GEPI5>3.0.CO;2-Y. PMID 9358268.
- ↑ 4.0 4.1 4.2 Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Friedman JM. PMID 20301288. Vancouver style error: initials (help); Missing or empty
|title=(help) - ↑ Upadhyaya M, Majounie E, Thompson P, Han S, Consoli C, Krawczak M, Cordeiro I, Cooper DN (January 2003). “Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1”. Hum. Genet. 112 (1): 12–7. doi:10.1007/s00439-002-0840-1. PMID 12483293.
- ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 “www.orpha.net” (PDF).
- ↑ “Epidemiology of neurofibromatosis type 1 (NF1) in northern Finland | Journal of Medical Genetics”.
- ↑ 8.0 8.1 Invalid
<ref>tag; no text was provided for refs namedpmid20301288 - ↑ 9.0 9.1 “Neurofibromatosis type 1 – Genetics Home Reference – NIH”.
- ↑ Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ (February 2017). “Neurofibromatosis type 1”. Nat Rev Dis Primers. 3: 17004. doi:10.1038/nrdp.2017.4. PMID 28230061.
- ↑ Huson SM, Compston DA, Clark P, Harper PS (November 1989). “A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity”. J. Med. Genet. 26 (11): 704–11. doi:10.1136/jmg.26.11.704. PMC 1015740. PMID 2511318.
- ↑ Thiel C, Wilken M, Zenker M, Sticht H, Fahsold R, Gusek-Schneider GC, Rauch A (June 2009). “Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome”. Am. J. Med. Genet. A. 149A (6): 1263–7. doi:10.1002/ajmg.a.32837. PMID 19449407.
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