Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing

Evans, D. Gareth; Hartley, Claire; Smith, Philip T.; King, Andrew T.; Bowers, Naomi L.; Tobi, Simon; Wallace, Andrew; Perry, Matthew Wray; Anup, Raji; Lloyd, Simon; Rutherford, Scott; Hammerbeck-Ward, Charlotte; Pathmanaban, Omar; Stapleton, Emma; Freeman, Simon; Kellett, Mark; Halliday, Dorothy; Parry, Allyson; Gair, Juliette; Axon, Patrick; Laitt, Roger; Thomas, Owen; Afridi, Shazia; Obholzer, Rupert; Duff, Chris; Stivaros, Stavros; Vassallo, Grace; Harkness, Elaine F.; Smith, Miriam J.

doi:10.1038/s41436-019-0598-7

Cited by 69 publications

(71 citation statements)

References 26 publications

(36 reference statements)

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“…Lymphocyte variant detection rates vary based on founder versus non‐founder status because of the high rate of somatic mosaicism in NF2. Although many reports have published somatic mosaicism in up to 30% of simplex cases (Moyhuddin et al., 2003), the recent use of next‐generation sequencing suggests mosaicism to be as high as 60% in first‐generation affected individuals (Evans, Hartley et al, 2019; Evans et al, 2019). Therefore, careful consideration of laboratory methodology and cautious interpretation of seemingly uninformative results are necessary.…”

Section: Genetic Counseling Processmentioning

confidence: 99%

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis—Practice Resource of the National Society of Genetic Counselors

Radtke

Bergner

Goetsch

et al. 2020

Journal of Genetic Counseling

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The goal of this practice resource is to provide genetic counselors and other healthcare professionals with a resource to reference when providing genetic counseling services to individuals and families undergoing evaluation for neurofibromatosis (NF) or who have received a diagnosis of NF, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). Currently, there is no known standard approach to genetic counseling in NF. This resource may be useful in a number of different healthcare settings. 1.1.1 | Pediatric or adult genetic counseling session (general genetics or specialty clinic) These sessions may occur in conjunction with a diagnosing provider, such as a physician or nurse practitioner. • Diagnostic evaluation based on clinical features and/or family history.

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Section: Genetic Counseling Processmentioning

confidence: 99%

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis—Practice Resource of the National Society of Genetic Counselors

Radtke

Bergner

Goetsch

et al. 2020

Journal of Genetic Counseling

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show abstract

“…Providing these has become straightforward since moving from Sanger to Next Generation sequencing (NGS) where identification of low DNA allele frequencies has been substantially enhanced. This has been shown to be very valuable in identifying underlying mosaic variants in monogenic conditions such as NF2 [34]. However, there is a particular pitfall in TP53 testing as well as for a number of other genes such as PPM1D and several oncogenes.…”

Section: Tp53 Allele Frequencymentioning

confidence: 99%

New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer

Evans

Woodward

2020

Familial Cancer

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“…Our studies on neurofibromatosis type 1 (NF1; MIM# 162200) and type 2 (NF2; MIM# 10100), which are two distinct tumor suppressor gene disorders, have revealed frequent mosaicism among de novo patients (Kehrer‐Sawatzki et al, 2004; Kluwe et al, 2003). A recent study estimated a 60% frequency for mosaicism in de novo NF2 patients (Evans et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Null phenotype of neurofibromatosis type 1 in a carrier of a heterozygous atypical NF1 deletion due to mosaicism

et al. 2020

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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.

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Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing

Cited by 69 publications

References 26 publications

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis—Practice Resource of the National Society of Genetic Counselors

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis—Practice Resource of the National Society of Genetic Counselors

New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer

Null phenotype of neurofibromatosis type 1 in a carrier of a heterozygous atypical NF1 deletion due to mosaicism

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