The missense p.Trp7Arg mutation in GRN gene leads to progranulin haploinsufficiency

GRN null mutations are among the main genetic causes of frontotemporal dementia through progranulin haploinsufficiency. Most missense mutations are considered not pathogenic. The p.Trp7Arg substitution is localized within the signal peptide domain and no formal evidence for its pathogenicity has yet been provided. We identified the p.Trp7Arg substitution in 3 carriers with low plasma progranulin levels. This evidences that this missense mutation leads to functional haploinsufficiency and should thus be considered pathogenic. Assessing the pathogenicity of variants of unknown significance has significant implications for clinical practice, genetic counseling, and future therapeutic interventions.