This is a guest post by Petra Pasanen, MSc from the University of Turku, Finland and a visiting fellow at TheGBLab.
In a collaboration between Adjunct Professor Liisa Myllykangas’ group and the GBLab we identified a novel genomic deletion underlying primary familial brain calcification (PFBC) [PMID 27726124]. This rare neurological disease is typically caused by mutations in SLC20A2, PDGFB, PDGFRB or XPR1. We studied a Finnish family with three affected subjects and five unaffected family members. Initial exome sequencing failed to detect any pathogenic variants. To locate the mutation, we sequenced the entire genomes of one affected patient and an unaffected family member.
Analysis of the whole genome sequencing data showed that the affected patient had a deletion of ~578 kb on chromosome 8p11.2, removing the first noncoding exon and 5’ noncoding regions of SLC20A2, the most commonly mutated disease gene in PFBC. In general, one can assume that no transcript is produced when the promoter region of a gene is missing, and we believe that this deletion causes disease by reducing the expression of SLC20A2. A SNP array was used to assess segregation in the family. The deletion was seen in the two affected patients and none of the unaffected family members (Figure).
Figure: Brain CT of patient II:2 showing calcification (marked with arrows) in basal ganglia and cerebellum and pedigree of the family with screenshots of SNP array data and the deletion breakpoint in SLC20A2 in WGS data visualized using the Integrative Genomics Viewer (IGV).
In addition to 5’ region of SLC20A2, the deletion abolishes the coding regions of six other genes (SMIM19, CHRNB3, CHRNA6, THAP1, RNF170, and HOOK3) and part of FNTA. It is currently not known if this has any additional effect on the clinical picture of the patients.
Our results highlight the need for analyzing copy number variations in known disease genes. Importantly, copy number variations can also affect the regulatory regions, as shown here. Our findings suggest that deletion of 5’ noncoding regions (including the putative promoter) of SLC20A2 is sufficient to cause PFBC.