Co‐occurring mutations of optineurin (OPTN) and colony‐stimulating factor‐1 receptor (CSF1R) genes in a family with familial frontotemporal dementia

Abstract

Background We report the clinical profiles and genetics of multiple family members from Samar, Philippines presenting with varying phenotypes of frontotemporal dementia. Literature studies report three gene mutations associated with a majority of fFTD cases, namely the microtubule associated protein tau gene (MAPT), and progranulin gene (PGRN), chromosome 9 open reading frame 72 (C9ORF72). These were all excluded in our case. Methods Clinical examination, Cranial MRI, and FDG‐PET were done. Genomic DNA was extracted from blood samples and analyzed via targeted exome sequencing. Result A frameshift mutation in the Optineurin (OPTN Chr 10:13166090 G>GA) was identified in multiple family members. This mutation is absent in public large international databases. Clinical and genetic studies show that frontotemporal dementia and motor neuron disease, in particular amyotrophic lateral sclerosis, are part of a disease spectrum with a common pathogenesis. However, there was no clinical or diagnostic evidence of motor neuron disease in family members with Optineurin mutations. A second mutation‐ missense mutation in the Colony‐Stimulating Factor‐1R V235G genes was seen in several family members. Colony‐Stimulating Factor‐1R gene mutations are associated with leukodystrophies when occurring singly. Clinical presentation and diagnostic tests did not support any of these findings. Conclusion At present, this is the only reported family with such combined mutations and genotype‐phenotype discordance. We are further investigating this family by conducting whole exome sequencing.