Skip to main content

Children’s Tumor Foundation Funded Research Demonstrates Important Genotype-Phenotype Correlation in Neurofibromatosis

By December 28, 2017December 5th, 2023CTF in the News, NF1, Press Release, Publications

Research funded by the Children’s Tumor Foundation (CTF) and led by Ludwine Messiaen, PhD, professor of genetics at the University of Alabama at Birmingham (UAB), has shown 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 disorder neurofibromatosis (NF) type 1, thereby improving the predictability of this condition when these specific mutations are present in an individual. This work was published today in the American Journal of Human Genetics.

Patients with NF1, or the parents of these patients, are often told to ‘watch and wait’ as there is no way to predict the path the NF1 diagnosis will take. NF1 occurs in 1 in 3,000 births across all populations, and causes tumors to grow on the nerves in the body. Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots, skin-fold freckling and multiple benign skin neurofibromas. Fifteen to thirty percent of individuals with NF1 have clinically apparent plexiform neurofibromas, at risk to become malignant. Learning disabilities are also common. Other potentially serious manifestations include optic nerve and other central nervous system gliomas, scoliosis and other bone abnormalities. There is currently no way to predict the outcome, thereby complicating treatment options. Besides the well-known variability of symptoms, even within the same family, detection of potential correlations between these symptoms and the inherited NF1 mutation (genotype) is complicated by the large size of the NF1 gene, and the thousands of different mutations that can lead to a variety of manifestations and symptoms in patients, some of these signs being age-related.

Dr. Messiaen has a long standing interest in genotype-phenotype correlations and currently has identified NF1 mutations (genotype) and associated symptoms (phenotype) in  over 8,100 unrelated NF1 individuals. The Children’s Tumor Foundation decided to invest in Dr. Messiaen’s promising work by providing Dr. Messiaen with the Isaac and Sadie Fuchs Genotype-Phenotype Grant to in order to facilitate the discovery of additional NF1 genotype-phenotype correlations. Dr. Messiaen heads the Medical Genomics Laboratory at UAB and is a recognized leader in genetic testing. As part of the NF1 genetic analysis at UAB, referring physicians complete a phenotypic checklist upon submission of a sample. This increases the understanding and awareness of the complexity and variability of NF1-associated signs and helps with the identification of potential genotype-phenotype correlations.

Such information is vital to helping guide clinical management and genetic counseling in this complex disease that can be caused by the thousands of different mutations found in every part of this large NF1 gene. This particular study shows a potential need for increased disease surveillance of patients with missense mutations in the cluster of codons 844 to 848. 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.

Individuals with such mutations, Dr. Messiaen and her team found, 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 higher predisposition to develop malignancies, compared with the general neurofibromatosis population.The protein encoded by NF1 is a string of 2,818 amino acids that folds into the protein shape. Although the NF1 gene was cloned in 1990, the cellular functions performed by the huge, multi-domain protein encoded by the gene, and called neurofibromin, are still incompletely understood. As such, the specific function of the NF1 codons 844-848 remains so far unknown.

Finding these correlations is important because whether patients will have mild or severe disease cannot — in most cases — be predicted when NF1 signs first appear, often only with café-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.

Patients vary widely in their symptoms, which can include freckles near skin folds of the body, nodules in the eyes, tumors along the optic nerve, heart defects, bone anomalies, developmental delay, intellectual disability and learning problems.

“It is important for people to know what may happen,” Dr. Messiaen said. “When a child is born with neurofibromatosis type 1, café-au-lait spots appear very shortly after birth. But other problems, more specifically the development of skin neurofibromas, typically appear around puberty. If a genotype-phenotype correlation exists for a particular mutation, it will help these families have some perspective of what the future will bring, and it will help families cope with the disease.”

Annette Bakker, PhD, President and Chief Scientific Officer of the Children’s Tumor Foundation outlined how this research will serve the NF1 population in three important ways, “First, it will allow a better understanding of the biological targets for treatments, and in turn help us develop better treatments for NF1. Second, it will help inform clinicians which patients are the best candidates for clinical trials,” Dr. Bakker continued, “and third, it will provide individuals and their families a better idea of which health concerns to monitor most closely – and to receive preventative care for.”

This study was the largest undertaking of its kind thus far, involving 162 NF1 codon 844-848 missense mutation-positive individuals, 75 researchers and clinicians from 46 hospitals and universities across 11 countries.  The missense mutations affecting codons 844-848 in the NF1 gene are found in about 0.8 percent of the mutation-positive probands in the UAB 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 percent 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 also may herald the potential for genotype-driven personalized 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 NF clinicians and molecular geneticists.

“Patients can help this process by joining the NF Registry ( and providing self-reported information about their NF, as well as increasing the likelihood of being called upon to participate in future clinical studies,” Dr. Bakker said.

To read the publication of this study by the American Journal of Human Genetics, please visit:

To read the University of Alabama press release, please visit:

To learn more about the Children’s Tumor Foundation, please visit