Ludwine Messiaen led the research at the University of Alabama at Birmingham, shows that missense mutations in a cluster of just five codons in the NF1 gene are an important risk factor for severe symptoms of the genetic disease neurofibromatosis type 1.The study was published in the American Journal of Human Genetics . It shows a potential need for increased disease surveillance of patients with missense mutations in that cluster.

Such Individuals with mutations, found the Researchers, have a high incidence of benign tumors of peripheral nerves or the spinal cord, tumors of the optic nerve, and skeletal abnormalities. They also have a high predisposition to develop malignancies, compared with the general neurofibromatosis population.

A missense mutation is a change in one nucleotide in DNA that results in a codon for a different amino acid in the protein made by the gene. This new study is just the fourth association between specific mutations and specific symptoms that have been discovered for neurofibromatosis type 1. Such an association is known as a genotype-phenotype correlation .

Finding these correlations is important because if patients will have mild or severe disease can not be predicted when the neurofibromatosis type 1 first appears, often only with coffee-au-lait skin markings in infants. As the patients grow, they show a broad clinical variability, especially beginning at puberty, when many develop benign skin tumors called neurofibromas that erupt as bumps across the body

The initial characterization of 78 individuals in the Medical Genomics Laboratory cohort with mutations affecting the amino acids 844-848 led to the identification of a genotype correlation and the study was further expanded to include another 84 individuals from collaborating centers. 

Neurofibromatosis type 1 is a common genetic disorder with highly variable symptoms, and it occurs in one out of every 2,000 to 3,000 births. The kaleidoscope of clinical signs in neurofibromatosis type 1 is mirrored by an abundance of different mutations in the NF1 gene.

The UAB Medical Genomics Laboratory has collected DNA and identified a pathogenic mutation on the more than 8,100 unrelated neurofibromatosis type 1 patients. These include more than 3,000 different mutations, and the mutational spectrum involves microdeletions, deletions or duplications of one or more exons, frameshift and nonsense mutations, and splice or missense mutations.

The missense mutations affecting codons 844-848 in the NF1 gene are found in about 0.8% of the mutation-positive probands in the UAB MGL cohort. Although only four groups of recurrent mutations with clear genotype-phenotype correlations have so far been reported, each of them affecting only a small percentage of NF1-affected individuals, they together affect between 5 and 10% of the neurofibromatosis type 1 population. While this is already a significant fraction of patients, Messiaen said the "surface has only been scratched."

While the present study suggests a potential need for increased disease surveillance in individuals with missense mutations affecting amino acids 844-848, it is also a potential for genotype-driven medicine. A renewed interest in genotype-phenotype correlations is needed to achieve a timely unfolding of additional correlations, and this will require close collaboration between NF1 clinicians and molecular geneticists.