Authors Koczkowska M. et al, American Journal of Human Genetics

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Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2000-3000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons Leu844, Cys845, Ala846, Leu847 and Gly848, located in the Cysteine-Serine-Rich Domain (CSRD). Collectively, these recurrent missense mutations affect ~0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1 cohorts (both p<0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1 population (p=0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

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Click here to find a recent article regarding the ongoing research in the neurofibromatoses taking place in the Medical Genomics Laboratory.
Click here for a summary of the findings and a link to article.
We provide a comprehensive panel that includes sequencing and deletion/duplication analysis for the TSC1 and TSC2 gene. Single gene sequencing and deletion/duplication analysis is also available for each of the genes within our panels, however our panel provides a cost-effective method to obtain a result for your patient without the necessity of ordering multiple tests.
The study led and coordinated by Ludwine Messiaen, PhD, director of the UAB Medical Genomics Laboratory and Arkadiusz Piotrowski, PhD, Children’s Tumor Foundation Young Investigator Awardee was published in the February 2014 issue of Nature Genetics. For more information regarding the findings of this study, please click here.