Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis : what should be offered?
Garcia, Belen (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Catasus, Núria (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Ros Peña, Andrea (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Rosas, Inma (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Negro, Alejandro (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Guerrero Murillo, Mercedes (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Valero, Ana Maria (Hospital Universitario Ramón y Cajal (Madrid))
Duat, Anna (Hospital Infantil Universitario Niño Jesús (Madrid))
Bonache, Sandra (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Lázaro García, Conxi (Institut d'Investigació Biomèdica de Bellvitge)
Comas, Carmina (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Bielsa, Isabel (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Serra, Eduard (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Hernández-Chico, Concepción (Hospital Universitario Ramón y Cajal (Madrid))
Martin, Yolanda (Hospital Universitario Ramón y Cajal (Madrid))
Castellanos, Elisabeth (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Blanco Guillermo, Ignacio (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Data:	2022
Resum:	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, 20 times higher than the NF1 mutation rate (~2×10) (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.
Ajuts:	Instituto de Salud Carlos III PI20/00215 Generalitat de Catalunya 2017/SGR-00496
Nota:	Altres ajuts: Fundació La Marató de TV3 (126/C/2020)
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Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Publicat a:	Journal of medical genetics, Vol. 59, Num. 10 (October 2022) , p. 1017-1023, ISSN 1468-6244

DOI: 10.1136/jmedgenet-2021-108301

Postprint 14 p, 481.9 KB

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