Analysis Of Secondary Causes In Fahr's Syndrome And Whole Exome Sequencing In Fahr Disease

Background & Objective:Ambiguous definition of Fahr syndrome is a neurological disorder characterized by calcification of bilateral symmetrical basal ganglia and other regions of the brain with a variety of movement disorders,cognitive decline and psychiatric disorders such as Parkinsonian symptoms,ataxia,dystonia,dementia,memory loss,confusion,and affective disorders,as well as epilepsy,headache,and other symptoms,or without any symptoms.However,in general,Fahr syndrome indicates basal ganlia calcification with secondary causes,while Fahr disease refers to primary or idiopathic calcification.The most common cause of Fahr syndrome is parathyroid disease,but mitochondrial,infectious,neurodegenerative,congenital,and systemic diseases,trauma,intoxication,physical therapy and age can be also observed.In clinical practice,Fahr syndrome with specific CT findings makes radiological diagnosis easy,but it is challenging to find out causative factors.Fahr disease has some familial genetic predisposition and is often referred to as IBGC or primary familial brain calcification(PFBC).To date,there are four pathogenic genes reported-SLC20A2,PDGFRB,PDGFB and XPR1.To our knowledge,IBGC-related genes in Asia are mostly SLC20A2,but mutations in PDGFRB and PDGFB have been rarely reported in China.In this study,patients with Fahr syndrome were analyzed for etiology,and genetic testing was performed for patients with Fahr disease from Northeast China and South Korea,whilst the correlation between genotype and phenotype was investigated.Methods:We screened 115 patients with pathological bilateral basal ganglia calcification by brain images at 2 affiliated hospitals of Jilin university in China and Seoul National University Hopital in Korea.We identified 56 patients with secondary causes which would be further classified,23 patients with Fahr disease(21 sporadic and 2 familial cases),uncertained remaining patients without sufficient clinical data.Of 23 patients with Fahr disease,4 were Chinese and 19 were Korean.Genetic testing was performed on these patients with Fahr disease by whole exome sequencing(WES).Results:Of the 56 patients with secondary causes,44 with parathyroid disease,3 with systemic lupus erythematosus,3 with carbon monoxide poisoning,3 with mitochondrial,1 with traumatic,and 2 with congenital were identified.For 23 patients with Fahr disease,we found 3 sporadic cases with de novo heterozygous pathogenic c.730+1G>T,c.1821G>A(p.W607X)and c.971C>A(p.S324X)variants in SLC20A2,and 2sporadic cases with reported SLC20A2 heterozygous likely pathogenic c.82G>A(p.D28N)and c.1703C> T(p.P568L)variants in SLC20A2 from South Korea.In addition,we identified four heterozygous variants of uncertain significance(VUS),c.301T>G(p.W101G)in SLC20A2,c.211G>C(p.G71R)and c.610C>A in PDGFB(p.P204T)and c.2053C>T(p.R685C)in PDGFRB.Conclusions:The etiologies of Fahr syndrome are diverse and make clinicians challenging to identify,the most common of wich is hypoparathyroidism.This is the first report of genetically confirmed Fahr disease in South Korea.We report three de novo mutations,c.730+1G>T,c.1821G>A,and c.971C>A,in SLC20A2 gene in South Korea.These findings expand the mutation spectrum of SLC20A2 was and provides an opportunity to further study the mechanism of calcification in Fahr disease.