High frequency of progranulin mutations in Caribbean Hispanic families with dementia

Background Progranulin ( GRN ) mutations cause frontotemporal dementia (FTD) and have been implicated in causing a variety of clinical neuro‐degenerative syndromes, including Alzheimer’s disease (AD) but it is hypothesized that these presentations all result from TDP‐43 pathology. We estimated the frequency of GRN mutations in multiplex families with dementia in the Dominican Republic and in New York. Methods We analyzed GRN mutations from whole genome sequencing data in 1941 individuals from 307 multiplex Caribbean Hispanic families with dementia. We prioritized rare (MAF<0.05 in GnomAD exomes and genomes) GRN variants annotated as having moderate‐high functional effect. Identified variants were cross‐referenced with FTD mutations found in Orphanet, MedGen, SNOMED and OMIM databases. GRN mutation carriers further were assessed for clinical and behavioral symptoms. Results We identified 27 rare, moderate‐high impact variants in GRN in the Caribbean Hispanic families. Six mutations (rs63750723, rs368705304, rs63750479, rs63750412, rs63751294, rs25647) were previously reported as associated with FTD and were found with MAF<0.05 in the GnomAD genomes. 92 individuals (4.7%) from 45 families carried at least one of the six previously reported GRN variants. Of these 47 (51 %) were initially thought to have Alzheimer’s Disease with an average age at onset of 77.8 (±8.93) and the remaining 46 were unaffected (average age of last healthy exam= 65.05 (±8.4)). Aggression and psychosis were frequently observed behavioral symptoms in the demented patients consistent with FTD phenotype. Conclusions In this study we observed a higher than expected frequency of damaging GRN mutations in families multiply affected by dementia. The majority of demented individuals were thought to have Alzheimer’s disease initially. Further analyses of phenotype‐genotype correlations should provide insight into impact of GRN mutations among Caribbean Hispanics.