PT - JOURNAL ARTICLE AU - Belen Garcia AU - Nuria Catasus AU - Andrea Ros AU - Inma Rosas AU - Alejandro Negro AU - Mercedes Guerrero-Murillo AU - Ana Maria Valero AU - Anna Duat-Rodriguez AU - Juan Luis Becerra AU - Sandra Bonache AU - Conxi Lázaro Garcia AU - Carmina Comas AU - Isabel Bielsa AU - Eduard Serra AU - Concepción Hernández-Chico AU - Yolanda Martin AU - Elisabeth Castellanos AU - Ignacio Blanco TI - Neurofibromatosis type 1 families with first-degree relatives harbouring distinct <em>NF1</em> pathogenic variants. Genetic counselling and familial diagnosis: what should be offered? AID - 10.1136/jmedgenet-2021-108301 DP - 2022 Oct 01 TA - Journal of Medical Genetics PG - 1017--1023 VI - 59 IP - 10 4099 - http://jmg.bmj.com/content/59/10/1017.short 4100 - http://jmg.bmj.com/content/59/10/1017.full SO - J Med Genet2022 Oct 01; 59 AB - 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.All data relevant to the study are included in the article or uploaded as supplementary information.