Null phenotype of neurofibromatosis type 1 in a carrier of a heterozygous atypical NF1 deletion due to mosaicism.
NF1 deletion
lipoma
mosaicism
neurofibromatosis type 1
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
05
11
2019
revised:
02
03
2020
accepted:
28
03
2020
pubmed:
6
4
2020
medline:
6
11
2021
entrez:
6
4
2020
Statut:
ppublish
Résumé
We coincidently detected an atypical deletion of at least 1.3-Mb, encompassing the NF1 tumor suppressor gene and several adjacent genes at an apparent heterozygous level in the blood of a 65-year-old female patient. She had multiple subcutaneous tumors that appeared with a certain similarity of subcutaneous neurofibromas, which, however, was revealed as lipomas by histological examination. Comprehensive and exhaustive clinical and radiological examinations did not detect any neurofibromatosis type 1-related clinical symptoms in the patient. Multiplex ligation-dependent probe amplification detected no or only very low level of the 1.3-Mb NF1 deletion in six lipomas and two skin biopsies. Digital polymerase chain reaction estimated the proportion of cells carrying a heterozygous NF1 deletion at 87% in the blood, and 8%, 10%, 13%, 17%, and 20%, respectively, in the five lipomas investigated by this method, confirming our hypothesis of mosaicism. Our findings suggest that de novo cases of genetic disease are potentially mosaic regardless of finding the mutation at an apparently heterozygous level in the blood and that the possibility of mosaicism should be considered in genotype-phenotype studies and genetic counseling.
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1226-1231Informations de copyright
© 2020 The Authors. Human Mutation Published by Wiley Periodicals, Inc.
Références
Campbell, I. M., Shaw, C. A., Stankiewicz, P., & Lupski, J. R. (2015). Somatic mosaicism: Implications for disease and transmission genetics. Trends in Genetics, 31, 382-392. https://doi.org/10.1016/j.tig.2015.03.013
Enzi, G., Busetto, L., Ceschin, E., Coin, A., Digito, M., & Pigozzo, S. (2002). Multiple symmetric lipomatosis: Clinical aspects and outcome in a long-term longitudinal study. International Journal of Obesity and Related Metabolic Disorders, 26, 253-261.
Evans, D. G., Hartley, C. L., Smith, P. T., King, A. T., Bowers, N. L., Tobi, S., … Obholzer, R., English Specialist NF research group. (2019). Incidence of mosaicism in 1055 de novo NF2 cases: Much higher than previous estimates with high utility of next-generation sequencing. Genetics in Medicine, 22, 53-59. https://doi.org/10.1038/s41436-019-0598-7
Gieldon, L., Masjkur, J. R., Richter, S., Därr, R., Lahera, M., Aust, D., … Klink, B. (2018). Next-generation panel sequencing identifies NF1 germline mutations in three patients with pheochromocytoma but no clinical diagnosis of neurofibromatosis type 1. European Journal of Endocrinology, 178, K1-K9. https://doi.org/10.1530/EJE-17-0714
Kehrer-Sawatzki, H., Kluwe, L., Sandig, C., Kohn, M., Wimmer, K., Krammer, U., … Mautner, V. F. (2004). High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene. American Journal of Human Genetics, 75, 410-423.
Kehrer-Sawatzki, H., Mautner, V. F., & Cooper, D. N. (2017). Emerging genotype-phenotype relationships in patients with large NF1 deletions. Human Genetics, 136, 349-376. https://doi.org/10.1007/s00439-017-1766-y
Kluwe, L. (2016). Digital PCR for discriminating mosaic deletions and for determining proportion of tumor cells in specimen. European Journal of Human Genetics, 24, 1644-1648. https://doi.org/10.1038/ejhg.2016.56
Kluwe, L., Mautner, V., Heinrich, B., Dezube, R., Jacoby, L. B., Friedrich, R. E., & MacCollin, M. (2003). Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. Journal of Medical Genetics, 40, 109-114.
Messiaen, L. M., Callens, T., Mortier, G., Beysen, D., Vandenbroucke, I., Van Roy, N., … Paepe, A. D. (2000). Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Human Mutation, 15, 541-555.
Parisien-La Salle, S., Dumas, N., Rondeau, G., Latour, M., & Bourdeau, I. (2019). Isolated pheochromocytoma in a 73-year-old man with no clinical manifestations of type 1 neurofibromatosis carrying an unsuspected deletion of the entire NF1 gene. Frontiers in Endocrinology, 10, 546. https://doi.org/10.3389/fendo.2019.00546
Roehl, A. C., Mussotter, T., Cooper, D. N., Kluwe, L., Wimmer, K., Högel, J., … Kehrer-Sawatzki, H. (2012). Tissue-specific differences in the proportion of mosaic large NF1 deletions are suggestive of a selective growth advantage of hematopoietic del(+/-) stem cells. Human Mutation, 33, 541-550.
Steinmann, K., Cooper, D. N., Kluwe, L., Chuzhanova, N. A., Senger, C., Serra, E., … Kehrer-Sawatzki, H. (2007). Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination. American Journal of Human Genetics, 81, 1201-1220.
Vogt, J., Bengesser, K., Claes, K. B., Wimmer, K., Mautner, V. F., van Minkelen, R., … Kehrer-Sawatzki, H. (2014). SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints. Genome Biology, 15, R80. https://doi.org/10.1186/gb-2014-15-6-r80
Vogt, J., Mussotter, T., Bengesser, K., Claes, K., Högel, J., Chuzhanova, N., … Kehrer-Sawatzki, H. (2012). Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder. Human Mutation, 33, 1599-1609. https://doi.org/10.1002/humu.22171