Using Repository of NF Mutations and Genomic Sequencing to Identify Novel Genes and Mutations Associated with NF

The UAB Medical Genomics Laboratory, directed by Ludwine Messiaen, Ph.D., offers clinical genetic testing for all rasopathies, including all the neurofibromatoses (NF1, NF-Noonan, spinal NF, segmental/mosaic NF1, NF2, schwannomatosis) and Legius syndrome. Besides the clinical activities, the laboratory is actively engaged in neurofibromatosis-related research through the pursuit of genotype-phenotype correlations and identification of novel disease-predisposing genes. The laboratory uses state-of-the-art genetic sequencing techniques that enable the precise identification and characterization of genetic mutations involved in these disorders.

Repository of NF Mutations

The UAB Medical Genomics Laboratory receives blood and tissue samples from patients referred by physicians around the world seeking to confirm a suspected diagnosis of neurofibromatosis. As a requirement for testing, a checklist documenting physical symptoms and characteristics (phenotypic checklist) is submitted along with the sample to be tested. Mining of the de-identified data related to more than 6,500 unrelated mutation-positive patients through an IRB-approved protocol allows genetic scientists to search for genotype-phenotype correlations. In addition, further IRB-approved studies in those patients without any mutation identified in the currently known NF-causing genes allow scientists to discover new disease-predisposing genes and delineate the spectrum of symptoms associated with mutations in a novel gene.

Discovery of the LZTR1  Gene Associated with Schwannomatosis

Using the approaches outlined above, a new gene that predisposes people to develop schwannomatosis, the third major form of neurofibromatosis, was recently identified. The first gene identified for schwannomatosis, located on chromosome 22, was discovered in 2007 by Hulsebos and colleagues. However, mutations in that gene were found in only 50% of familial schwannomatosis cases and less than 10% of sporadic cases. In an effort to identify a possible new gene, Drs. Messiaen, Piotrowski, and their colleagues designed a study that focused on tumor samples from a subset of people in the repository who showed characteristics of schwannomatosis but did not carry a mutation. Using next-generation sequencing of evolutionary conserved regions on chromosome 22, mutations in a new tumor-suppressor gene were found and shown to be the predisposing factors for the development of schwannomas in these patients. This breakthrough will help scientists design future studies to test potential drug treatments that target the function of both genes.

Learn more about the UAB Neurofibromatosis Program’s leading-edge research initiatives in the following areas:

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NF1 mouse
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Stem cell lines
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NF mutation repository
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Clinical trials consortium

For more information, please contact the UAB Neurofibromatosis Program at 205-934-4983.