Case Report: Two Novel Frameshift Mutations in and One Novel Splice Donor Mutation in Associated With Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC, OMIM#213600), also known as Fahr's disease, is characterized by bilateral and symmetric brain calcification in the basal ganglia (globus pallidus, caudate nucleus, and putamen), thalamus, subcortical white matter, and cerebellum. PFBC can be caused by loss-of-function mutations in any of the six known causative genes. The most common clinical manifestations include movement disorders, cognitive impairment, and neuropsychiatric signs that gradually emerge in middle-aged patients. To broaden the PFBC mutation spectrum, we examined nine members of a family with PFBC and two sporadic cases from clinical departments, and sequenced all PFBC-causative genes in the index case. Two novel frameshift mutations in [NM_001257180.2; c.806delC, p.(Pro269Glnfs49) and c.1154delG, p.(Ser385Ilefs70)] and one novel splice donor site mutation (NM_002608.4, c.456+1G>C, r.436_456del) in were identified in the patient cohort. c.806delC co-segregated with brain calcification and led to haploinsufficiency among the affected family members. The c.456+1G>C mutation in resulted in aberrant mRNA splicing, thereby forming mature transcripts containing an in-frame 21 base pair (bp) deletion, which might create a stably truncated protein [p.(Val146_Gln152del)] and exert a dominant negative effect on wild-type PDGFB. All three mutations were located in highly conserved regions among multiple species and predicted to be pathogenic, as evaluated by at least eight common genetic variation scoring systems. This study identified three novel mutations in and , which broadened and enriched the PFBC mutation spectrum.