Genetic Analysis Of MYORG Gene In Patients With Primary Familial Brain Calcification

Background:Primary familial brain calcification?PFBC?,previously known as Fahr's disease or idiopathic basal ganglia calcification,is a rare neuropsychiatric disorder characterized by bilateral calcification in the basal ganglia and other brain regions.PFBC is typically thought to be inherited as an autosomal-dominant trait and has thus far been associated with SLC20A2,PDGFB,PDGFRB or XPR1 mutations.Very recently biallelic mutations in the MYORG gene were identified as a novel genetic cause for autosomal recessive PFBC in twelve Chinese patients from six unrelated families.Larger-scale genetic studies are needed to establish the association between MYORG gene and primary familial brain calcification.Objective:To clarify the relationship between MYORG gene and Chinese patients with primary familial brain calcification.Methods:We collected clinical and neuroradiological data of 169 Chinese patients with primary familial brain calcification,including 151 sporadic patients and 18 patients from 13 families compatible with an autosomal recessive mode of inheritance.Exon regions and exon-intron boundaries of the MYORG gene were amplified by polymerase chain reaction?PCR?.PCR products were purified and directly sequenced to detect variants in MYORG gene.Results:Three novel mutations,c.1431 C>A?p.Y477*?,c.687G>T?p.W229C?,c.428₄42del TGCACTTCTTCATCC?p.143₁47delLHFFI?,and one known mutation,c.348₃49insCTGGCCTTCCGC?p.116₁17insLAFR?were detected in five patients.The 12-bp insertion c.348₃49insCTGGCCTTCCGC was found in either homozygous or heterozygous state in two probands of our cohort.Haplotype analysis of our patients harboring the insertion indicated a founder effect in ethnic Han Chinese population.To date,biallelic MYORG mutations have been reported in 17 patients?including our cohort?.Most patients were symptomatic?13/17,76.5%?and the most recurrent symptoms were movement disorders?10/17,58.8%?,cognitive decline?7/17,41.2%?and cerebellar symptoms?6/17,35.3%?.All patients had calcifications on comprehensive cranial computed tomography,most frequently located in the basal ganglia?17/17,100%?,cerebellum?17/17,100%?,subcortical white matter?14/17,82.4%?,and thalamus?13/17,76.5%?.Conclusion:We confirmed MYORG as a novel causative gene for PFBC and further expanded the mutational and phenotypic spectrum of MMORG-related PFBC.