Children’s Tumor Foundation Funded Research Demonstrates Important Genotype-Phenotype for a Three Base Pair Deletion in NF1

Sep 18, 2018

International collaborative research led by Ludwine Messiaen, PhD, shows that while a three-base pair, in-frame deletion called p.Met992del in the NF1 gene has a mild phenotype for people with the genetic disorder neurofibromatosis type 1, or NF1, the mutation does cause complications. These include non-optic brain tumors, mostly low-grade and asymptomatic, as well as cognitive impairment and/or learning disabilities. This study extends findings first reported in 2007 that included only 19 NF1 adults. Including more adults in the new study was the key to obtaining statistically significant evidence of a mild phenotype that included absence of cutaneous and externally visible plexiform neurofibromas and symptomatic optic pathway gliomas. This is important because whether patients will have mild or severe disease cannot — in most cases — be predicted when the neurofibromatosis type 1 first appears, often only with café-au-lait skin markings in infants. As the patients grow, they typically show a broad clinical variability. 

To look for correlations, Messiaen and her team collected detailed clinical information on all symptoms found in each of 135 NF1-affected individuals from 103 unrelated families who had the p.Met992del mutation identified at the UAB Medical Genomics Laboratory and collaborating European centers. Then, these data were compared to several large clinical cohorts previously reported in the literature.

Their study, published in the journal Genetics in Medicine, involved 70 researchers and clinicians from 47 hospitals and universities in the United States, Belgium, Italy, Spain, the Netherlands, Australia, Austria and Canada. That study can be accessed here. First author on the paper is Magdalena Koczkowska, PhD, a postdoctoral fellow who joined the UAB Medical Genomics Laboratory in 2016 to work on the identification of novel genotype-phenotype correlations in NF1. Dr. Messiaen heads the Medical Genomics Laboratory at UAB and is a recognized leader in genetic testing.

Dr. Messiaen has a long standing interest in genotype-phenotype correlations, and the Children’s Tumor Foundation has invested in Dr. Messiaen’s promising work by providing the Isaac and Sadie Fuchs Genotype-Phenotype Grant to in order to facilitate the discovery of additional NF1 genotype-phenotype correlations.

Read more about Dr. Messiaen's genotype-phenotype research in this recent news story from NF News here.