부산대학교 도서관

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1. Recently, NF1testing 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.Methods829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1familial variants was determined by microsatellite analysis and NF1sequencing.ResultsThe mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10–3, 20 times higher than the NF1mutation rate (~2×10−4) (p=0.0008). Furthermore, the co-occurrence of two different NF1germline 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.ConclusionsOur 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 NF1genetic testing.