Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1. Recently, NF1 testing has been included as a clinical criterion for NF1 diagnosis. Additionally, preconception genetic counselling in patients with NF1 focuses on a 50% risk of transmitting the familial variant as the risk of having a sporadic NF1 is considered the same as the general population.
Methods 829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1 familial variants was determined by microsatellite analysis and NF1 sequencing.
Results The mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1 germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10–3, 20 times higher than the NF1 mutation rate (~2×10−4) (p=0.0008). Furthermore, the co-occurrence of two different NF1 germline pathogenic variants in these families was 1:39, 60 times the frequency of sporadic NF1 (1:2500) (p=0.003). In all cases, the de novo NF1 pathogenic variant was present in a descendant of an affected male. In two cases, variants were detected in the inherited paternal wild-type allele.
Conclusions Our results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing.
- human genetics
- genetic counseling
- genetic testing
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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BG and NC are joint first authors.
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BG and NC contributed equally.
EC and IB contributed equally.
Contributors EC and IB designed the study and wrote the manuscript that was revised, corrected and improved by all authors. Both, EC and IB are the guarantors of this work. BG, NC and YM performed most of the experimental work and analysed the data. MG-M performed statistical analysis. IR, AN and AV performed genetic analysis. AR, AD, JLB, CC and IB contributed with clinical data collection. SB, CH-C, CLG and ES provided scientific input. NC generated the figures for the paper and contributed in writing the manuscript. All authors approved the final version of the manuscript.
Funding This work has been supported by The Children’s TumorTumour Foundation (CTF-2019-05-005), the Spanish Association of NF Affected (AANF), Fundación Proyecto Neurofibromatosis, the Catalan NF Association (AcNeFi), the Ministry Science and Innovation (PI20/00 215); Fundació La Marató de TV3 (126/C /C/2020) and the Generalitat of Catalonia (2017 SGR 496).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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