Protein domain-specific genotype-phenotype correlation study of neurofibromatosis type 1.

Neurofibromatosis type 1 (OMIM 613,113, NF1) is a neurocutaneous disorder caused by pathogenic genetic alteration in NF1 gene, which exhibits nearly full penetrance and affects multiple systems. Previously two association studies of optic pathway glioma and NF1 protein domains, derived from 215 and 381 patients, respectively, obtained contradicting results, reflecting different datasets can lead to different conclusions and there is a need for a larger dataset to reach a solid conclusion. There is another association study based on 832 patients considering protein domains, clinical features, and types of variants. But it only investigated the GTPase-activating protein domain and non-truncating variants. In this study, an extended association analysis involving eight protein domains, two types of variants, namely truncating and non-truncating variants, and 32 clinical features, was performed based on a combined dataset of 1663 NF1 patients consisting of 738 cases recruited in Hong Kong and 925 reported cases from 25 studies. In summary, this study has identified 121 statistically significant associations between clinical features, types of variants, and protein domains, with 120 of them being novel findings. These new insights about the genotype–phenotype association promote better clinical management.