Hannie C W Douben, Mark Nellist, Leontine van Unen, Peter Elfferich, Esmee Kasteleijn, Marianne Hoogeveen-Westerveld, Jesse Louwen, Monique van Veghel-Plandsoen, Walter de Valk, Jasper J Saris, Femke Hendriks, Esther Korpershoek, Lies H Hoefsloot, Margreethe van Vliet, Yolande van Bever, Ingrid van de Laar, Emmelien Aten, Augusta M A Lachmeijer, Walter Taal, Lisa van den Bersselaar, Juliette Schuurmans, Rianne Oostenbrink, Rick van Minkelen, Yvette van Ierland, Tjakko J van Ham
Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in NF1. Due to the size, complexity and high mutation rate at the NF1 locus, the identification of causative variants can be challenging. To obtain a molecular diagnosis in 15 individuals meeting diagnostic criteria for NF1, we performed transcriptome analysis (RNA-seq) on RNA obtained from cultured skin fibroblasts. In each case routine molecular DNA diagnostics had failed to identify a disease-causing variant in NF1. A pathogenic variant or abnormal mRNA splicing was identified in 13 cases: 6 deep intronic variants and 2 transposon insertions causing non-canonical splicing, 3 post-zygotic changes, one branchpoint mutation and, in one case, abnormal splicing for which the responsible DNA change remains to be identified...
October 17, 2022: Human Mutation