Novel findings in a Swedish primary familial brain calcification cohort

Introduction Brain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial. This paper aims to characterize a Swedish PFBC cohort including 25 patients: 20 from seven families and five sporadic cases. Methods Longitudinal clinical assessment and CT imaging were conducted, abnormalities were assessed using the total calcification score (TCS). Genetic analyses, including a panel of six known PFBC genes, was performed in all index and sporadic cases. Additionally, three patients carrying a novel pathogenic copy number variant in SLC20A2 had their cerebrospinal fluid phosphate (CSF-Pi) levels measured. Results Among the 25 patients, the majority (76%) displayed varying symptoms during the initial assessment including motor (60%), psychiatric (40%), and/or cognitive abnormalities (24%). Clinical progression was observed in most patients (78.6%), but there was no significant difference in calcification between the first and second scans, with mean scores of 27.3 and 32.8, respectively. In three families and two sporadic cases, pathogenic genetic variants were identified, including a novel finding, in the SLC20A2 gene. In the three tested patients, the CSF-Pi levels were normal. Conclusions This report demonstrates the variable expressivity seen in PFBC and includes a novel pathogenic variant in the SLC20A2 gene. In four families and three sporadic cases, no pathogenic variants were found, suggesting that new PFBC genes remain to be discovered.