Digenic Variants as Possible Clinical Modifier of Primary Familial Brain Calcification Patients Rayssa Leal Borges-Medeiros 1 & João Ricardo Mendes de Oliveira 1,2 Received: 3 September 2019 /Accepted: 3 November 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Primary familial brain calcification (PFBC), widely known as Fahr’ s disease, is a rare disorder caused by pathogenic variants in SLC20A2, PDGFB, PDGFRB, XPR1, or MYORG genes. It is characterized by ectopic brain calcification, mostly affecting basal ganglia, thalamus, and cerebellum. PFBC patients can present a wide spectrum of symptoms including cognitive, neuropsychi- atric, and motor alterations. However, it is well established that PFBC individuals also present high clinical heterogeneity, though the genetic cause of this phenotypic is not understood. Recently, Wang et al. (Front Cell Neurosci. https://doi.org/10.3389/fncel. 2019.00250, 2019) reported on the role of MEA6 gene in cerebellar development and motor performance, also citing that MEA6 might be linked to PFBC. A MEA6 variant was described in 2007 as a PFBC candidate gene in an American family. However, this family was later linked to the SLC20A2 gene discarding the MEA6 as a PFBC-gene and also some members were confirmed as phenocopy. Additionally, five independent studies have been shown that variants in a second gene, not related to PFBC, were identified in PFBC patients, promoting a complex and heterogeneous phenotype. Thus, further investigation is required to explain whether and how MEA6 contributes to the clinical presentation in this American family. Finally, this letter highlights the possible digenic influence on clinical heterogeneity of PFBC patients, and such a possibility might advance our understanding of PFBC phenotypes. Keywords PFBC . Phenocopy . Digenic disease . MEA6 . SLC20A2 Dear Editor, Primary familial brain calcification (PFBC) is a rare neurode- generative disorder characterized by ectopic brain calcifica- tion with symmetrical and bilateral patterns affecting the basal ganglia and cerebellum (Quintáns et al. 2018). The pathophys- iology of PFBC has been linked to pathogenic variants in one of the five genes described until now (SLC20A2, PDGFB, PDGFRB, XPR1, and MYORG) (Wang et al. 2012; Keller et al. 2013; Nicolas et al. 2013; Legati et al. 2015; Yao et al. 2018). This disorder results in a complex clinical heterogene- ity that might include motor and neuropsychiatric symptoms (Quintáns et al. 2018). However, the genetic basis of this phenotypic PFBC heterogeneity is not understood and even not fully explained by a single variant. Recently, Wang et al. (2019) presented their findings on the MEA6 gene (MGEA6/CTAGE5) and its contribution to cere- bellar development and motor performance. They also report- ed that the MEA6 gene might be associated with PFBC (Wang et al. 2019). In 2018, Zhang et al. had also reported the pos- sible relationship between the MEA6 gene and PFBC, sug- gesting further research to confirm this association (Zhang et al. 2018). Such a possible association was first mentioned in 2007 when Oliveira et al. described a MEA6 variant (rs36060072; P521A; MAF < 0.01) that segregated in eleven members of the same family, all having PFBC phenotypes (Oliveira et al. 2007). Thus, the MEA6 was considered a can- didate gene for PFBC. However, it is important to highlight that the abovementioned family was afterward linked to the SLC20A2 PFBC-gene (c.508delT; p.L170*) (Geschwind et al. 1999; Oliveira et al. 2007; Hsu et al. 2013). It is also meaningful to mention that two of eleven members of this family, who were initially attributed to having PFBC, were considered as false positive after being genetically negative * João Ricardo Mendes de Oliveira joao.ricardo@ufpe.br 1 Keizo Asami Laboratory, Universidade Federal de Pernambuco, Recife, Brazil 2 Neuropsychiatric Department, Universidade Federal de Pernambuco, Av. Professor Moraes Rego, 1235, Cidade Universitária, Recife, Pernambuco 50670-901, Brazil https://doi.org/10.1007/s12031-019-01430-9 Journal of Molecular Neuroscience (2020) 70:142–144 /Published online: 25 November 2019