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Mutations in Cluster of NF1 Codons Associated With More Severe Neurofibromatosis

NEW YORK (GenomeWeb) – Certain mutations within the NF1 gene are associated with more severe neurofibromatosis type 1 symptoms, a new study has found.

NF1 is a common genetic disease, affecting one in every 2,000 to 3,000 births, that is caused by loss-of-function mutations in the NF1 gene. Patients' symptoms, though, can vary and may include freckles in skin folds, neurofibromas, developmental delay, and more.

Researchers led by University of Alabama at Birmingham's Ludwine Messiaen studied 162 people with NF1 who underwent clinical testing to pinpoint their mutation. As the researchers reported in the American Journal of Human Genetics, people with mutations within a cluster of five codons tended to have a more severe form of the condition.

"It is important for people to know what may happen," Messiaen said in a statement. "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."

Among 78 people who underwent molecular testing for NF1 at UAB, the researchers uncovered 35 unrelated people who had missense mutations in five codons within exon 21 of the NF1 gene. When the researchers expanded their cohort to include 84 people from other centers — for a total of 129 unrelated people and 33 affected relatives — they noted 12 different NF1 missense mutations in those neighboring codons. Messiaen and her colleagues estimated that these mutations are present in about 0.8 percent of unrelated NF1 mutation-positive individuals.

Of the 12 different missense mutations the researchers found within codons 844 through 848, eight were present within the Leiden Open Variation Database, which classified five of them as likely pathogenic. Eight of the missense mutations were also in the ClinVar database where three were classified as pathogenic and one as likely pathogenic. Through in silico analyses with SIFT and PolyPhen2, the researchers found that all these alterations were likely to be deleterious or probably or possibly damaging.

These five codons fall in a highly conserved cysteine-serine-rich domain encoded within the NF1 gene, the researchers noted. Codons 775 to 856 are fully conserved in chimpanzee, rat, and mouse, suggesting to Messiaen and her colleagues that they are functionally important.

The 129 unrelated people in this cohort were also phenotypically assessed using a standard checklist. That list included both general data such as birthday and height and weight, but also NF1-specific data such as the presence of café-au-lait macules, skin fold freckling, and neurofibromas.

By linking genotypes to phenotypes, Messiaen and her colleagues found that people with missense variants within codons 844 through 848 were more likely to have severe NF1 symptoms. For instance, nearly 80 percent of those over the age of nine had more than five café-au-lait macules or skin-fold freckling, almost 70 percent of those over the age of 19 had cutaneous neurofibromas, and about half had subcutaneous neurofibromas.

When they compared the incidence of symptoms in their population to the wider NF1 population, the researchers found their cohort had an increased number of major external plexiform neurofibromas. Clinically apparent plexiform neurofibromas are typically present in between 15 percent and 30 percent of the wider NF1 population, while they were present in 39 percent of the cohort studied here. Likewise, about 2 percent of the wider NF1 population develops symptomatic spinal neurofibromas, whereas 10 percent of this cohort did.

All in all, Messiaen and her colleagues estimated that three-quarters of adults with missense mutations in these codons have severe disease.

"These data suggest that there is a potential need for increased disease surveillance in individuals with these mutations enabling genotype-driven personalized medicine," the researchers wrote in their paper.