Germline mosaicism in neurofibromatosis type 1 due to a paternally derived multi‐exon deletion

Bottillo, Irene; Torrente, Isabella; Lanari, Valentina; Pinna, Valentina; Giustini, Sandra; Divona, Luigina; Luca, Alessandro De; Dallapiccola, Bruno

doi:10.1002/ajmg.a.33386

Cited by 28 publications

(12 citation statements)

References 49 publications

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“…In our data the observed transmission rate of 9 of 23 (39%) does not differ significantly from the expected risk of 50% in any autosomal disorder. The rate of transmission is in accordance with two previous reports where three of six and two of three siblings had NF1 in spite of a germ line mosaicisms of 10% and 10–17%, respectively . We have to take into account the limited size of our dataset.…”

Section: Discussionsupporting

confidence: 82%

Clinical presentations of 23 half‐siblings from a mosaic neurofibromatosis type 1 sperm donor

et al. 2015

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The Danish sperm donor number 7042 has fathered several offspring with neurofibromatosis type 1 (NF1) worldwide. NF1 is caused by loss-of-function mutations in the NF1 gene and more than 1000 NF1 mutations are identified. Analysis of the donor sperm demonstrated gonosomal mosaicism with an intragenic deletion involving exons 15-29 in the NF1 gene. At the two Danish reference centres for NF1 patients, we evaluated 23 half-siblings from the donor. Nine were diagnosed with NF1. The severity grade of NF1 progressed from minimal to mild/moderate within 3 years of follow-up. The NF1 phenotype shows great variability in intra- and inter-family expressivity and to date only two NF1 genotype-phenotype correlations have been established. This rare possibility of a long-term follow-up of a cohort of half-siblings with NF1 makes further studies including phenotypic variability and search for modifier genes possible. To achieve this goal, we have initiated The International Donor 7042 NF1 Offspring Registry. Research facilitated via this registry may reveal important new knowledge of clinical characteristics and prognostics for the specific NF1 genotype and thereby contribute to future individualised targeted clinical follow-up and treatment.

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Section: Discussionsupporting

confidence: 82%

Clinical presentations of 23 half‐siblings from a mosaic neurofibromatosis type 1 sperm donor

et al. 2015

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“…So far germline mosaicism in NF1 was demonstrated at the molecular level only in two reports (18,19); interestingly in both cases the mutation was found to derive from the father. To our knowledge, this is the first case of a maternal germline mosaicism and, conversely to the notion that most sporadic point mutations in NF1 arise in the paternally derived allele (20), we identified a splicing mutation originating from the maternal chromosome, that most likely arose in her germline since all other tested tissues were negative for the presence of the mutation.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism

et al. 2013

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Neurofibromatosis type 1 (NF1) is caused by loss of function mutations of the NF1 gene, which are de novo in 50% of cases. Although this gene shows one of the highest mutation rates in the human genome, germline mosaicism is very rare in this condition. We describe the molecular analysis of a family in which neurofibromatosis type 1 occurred in two out of four siblings born to unaffected parents. Molecular analysis of the NF1 gene identified in both patients the same splicing mutation c.1392+1G>A, which was absent in parental lymphocytes. Microsatellite analysis showed that the two affected siblings shared the same maternal allele, however a specific PCR-RFLP assay excluded the presence of the NF1 splicing mutation in multiple maternal tissues. Our molecular and clinical findings are consistent with a germline mosaicism for the NF1 splicing mutation. This is the first case of maternal germline mosaicism for a NF1 mutation characterized so far at the molecular level. Our data confirm that germline mosaicism is rare in neurofibromatosis 1, but it has important implications for genetic counseling.

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“…To date, only three NF1 families with gonadal or germline mosaicism have been reported [31–33]. In such families, only a small proportion of the germ cells, whether sperm or ova, will carry the new NF1 mutation, but this can nevertheless result in more than one affected child being produced by clinically normal parents [34].…”

Section: Introductionmentioning

confidence: 99%

The NF1 somatic mutational landscape in sporadic human cancers

et al. 2017

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BackgroundNeurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1.Main bodyCapitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context.ConclusionAs neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.

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Germline mosaicism in neurofibromatosis type 1 due to a paternally derived multi‐exon deletion

Cited by 28 publications

References 49 publications

Clinical presentations of 23 half‐siblings from a mosaic neurofibromatosis type 1 sperm donor

Clinical presentations of 23 half‐siblings from a mosaic neurofibromatosis type 1 sperm donor

Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism

The NF1 somatic mutational landscape in sporadic human cancers

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