Generalized epilepsy in a family with basal ganglia calcifications and mutations in SLC20A2 and CHRNB2

Abstract Background The genetic understanding of primary familial brain calcification (PFBC) has increased considerably in recent years due to the finding of causal genes like SLC20A2 , PDGFRB and PDGFB . The phenotype of PFBC is complex and has as of yet been poorly delineated. The most common clinical presentations include movement disorders, cognitive symptoms and psychiatric conditions. We report a family including two sisters with brain calcifications due to a variant in SLC20A2 and generalized tonic-clonic seizures as the principal phenotypic trait. Methods The affected siblings underwent whole exome sequencing and candidate variants and cosegregation in the family were validated by Sanger sequencing. Results Both siblings and their asymptomatic father were heterozygous for a variant in SLC20A2 . The siblings also had a variant in CHRNB2 , a known epilepsy gene associated with autosomal dominant frontal lobe epilepsy, which they had inherited from the mother. Conclusions To our knowledge, the reported siblings represent the third and fourth subjects with confirmed SLC20A2 variants exhibiting epilepsy as a phenotypic trait. Our findings support seizures as part of the phenotypic spectrum of SLC20A2- related PFBC. However, the present phenotype may also result from additional genetic influence, such as the identified missense variant in CHRNB2 .