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Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders
Open AccessArticle

One NF1 Mutation may Conceal Another

Service de Génétique et Biologie Moléculaires, Hôpital Cochin, HUPC, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France
Institut Cochin, INSERM U1016, Université Paris Descartes, 75014 Paris, France
Inserm, UMR 1231, Génétique des Anomalies du Développement, Université de Bourgogne, 21079 Dijon, France
Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d’Enfants, 21079 Dijon, France
Department of Child Neurology and National Reference Center for Neurogenetic Disorders, Armand Trousseau Hospital, GHUEP, AP-HP, INSERM U1141, 75012 Paris, France
GRC n°19 ConCer-LD, Sorbonne Université, 75012 Paris, France
Service de Génétique, CHRU de Tours, 37044 Tours, France
Centre de référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpital Civil, 67091 Strasbourg, France
Service de Génétique Médicale, Hôpital de Hautepierre, 67200 Strasbourg, France
Laboratoire de Génétique Médicale, INSERM U1112, 67000 Strasbourg, France
Service de Génétique, EA3808, Université de Poitiers, CHU de Poitiers, 86000 Poitiers, France
Department of Cytogenetics and clinical genetics, Limoges University Hospital, 87042 Limoges, France
UMR 7252, Limoges University, CNRS, XLIM, 87000 Limoges, France
EA 4537, Antilles University, 97261 Fort-de-France, Martinique, France
DRCI, Martinique University Hospital, 97261 Fort-de-France, Martinique, France
Author to whom correspondence should be addressed.
Genes 2019, 10(9), 633;
Received: 19 July 2019 / Revised: 10 August 2019 / Accepted: 20 August 2019 / Published: 22 August 2019
(This article belongs to the Special Issue Neurofibromatosis 1 Genetics)
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 NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 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 NF1 and SPRED1 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 NF1 variants. All NF1 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 NF1 gene from her mother and carried a variant of unknown significance in the SPRED1 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. View Full-Text
Keywords: de novo variant; Legius syndrome; neurofibromatosis type 1; NF1; SPRED1 de novo variant; Legius syndrome; neurofibromatosis type 1; NF1; SPRED1
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Pacot, L.; Burin des Roziers, C.; Laurendeau, I.; Briand-Suleau, A.; Coustier, A.; Mayard, T.; Tlemsani, C.; Faivre, L.; Thomas, Q.; Rodriguez, D.; Blesson, S.; Dollfus, H.; Muller, Y.-G.; Parfait, B.; Vidaud, M.; Gilbert-Dussardier, B.; Yardin, C.; Dauriat, B.; Derancourt, C.; Vidaud, D.; Pasmant, E. One NF1 Mutation may Conceal Another. Genes 2019, 10, 633.

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