One <i>NF1</i> Mutation may Conceal Another

• Main Authors: Laurence Pacot, Cyril Burin des Roziers, Ingrid Laurendeau, Audrey Briand-Suleau, Audrey Coustier, Théodora Mayard, Camille Tlemsani, Laurence Faivre, Quentin Thomas, Diana Rodriguez, Sophie Blesson, Hélène Dollfus, Yvon-Gauthier Muller, Béatrice Parfait, Michel Vidaud, Brigitte Gilbert-Dussardier, Catherine Yardin, Benjamin Dauriat, Christian Derancourt, Dominique Vidaud, Eric Pasmant
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: Genes
• Subjects: de novo variant; Legius syndrome; neurofibromatosis type 1; <i>NF1</i>; <i>SPRED1</i>
• Online Access: https://www.mdpi.com/2073-4425/10/9/633

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the <i>NF1</i> gene, a negative regulator of the RAS-MAPK pathway. The <i>NF1</i> gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the <i>NF1</i> and <i>SPRED1</i> genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent <i>NF1</i> variants. All <i>NF1</i> variants were classified as pathogenic, according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. In the sixth family, one sibling inherited a complete deletion of the <i>NF1</i> gene from her mother and carried a variant of unknown significance in the <i>SPRED1</i> gene. This variant was also present in her brother, who was diagnosed with Legius syndrome, a differential diagnosis of NF1. This work illustrates the complexity of molecular diagnosis in a not-so-rare genetic disease.