Idiopathic Basal Ganglia Calcification Panel

Idiopathic Basal Ganglia Calcification (IBGC), also known as Fahr’s syndrome, is a neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement. The radiological characteristics of IBGC consist of bilateral and symmetrical calcification of the basal ganglia. Additional areas of the brain may also be affected. IBGC is clinically heterogeneous. Symptoms usually begin during the fourth and fifth decades of life. Childhood and adolescent onset have also been reported. Movement disorders in the form of dystonia, tremor and chorea are the initial and most common clinical manifestations of IBGC. As the disease progresses, neurological and neuropsychiatric abnormalities are detected and include seizures, spasticity, headache, dysarthria, psychosis, mood disturbances, cognitive decline, and dementia (Manyam., 2005. PubMed ID: 15734663; Nicolas et al., 2013. PubMed ID: 24065723). Abnormal deposit of calcium in the brain is a common finding usually associated with aging. However, IBGC is rare, with less than 1/1,000,000 people affected worldwide (Ellie et al., 1989. PMID: 2927646). See also Sobrido et al., 2014. PMID: 20301594.

IBGC is genetically heterogeneous. Although most cases are familial with autosomal dominant inheritance, simplex cases with no apparent family history have been also reported. To date, four genes have been implicated in the disease: SLC20A2, PDGFB, PDGFRB and XPR1 (Wang et al., 2012. PubMed ID: 22327515; Keller et al., 2013. PubMed ID: 23913003; Nicolas et al., 2013. PubMed ID: 23255827; Legati et al., 2015. PubMed ID: 25938945).

About 85 pathogenic variants have been reported both in familial and apparently simplex cases from various ethnic and geographic populations (Human Gene Mutation Database).

About half of the variants in the SLC20A2 and PDGFB genes are missense. The other half consists of truncating variants and includes nonsense, splicing and small frameshift insertions and deletions (HGMD). Only one small deletion that is predicted to result in the in-frame deletion of one single amino acid has been reported in the SLC20A2 gene (Wang et al., 2012. PubMed ID: 22327515).

Pathogenic variants in the PDGFRB and XPR1 genes are all of the missense type (HGMD).

PDGFB encodes the platelet-derived growth factor beta (Keller et al., 2013. PubMed ID: 23913003). PDGFRB encodes its main receptor (Nicolas et al., 2013. PubMed ID: 24065723). It has been suggested that the PDGFRB/ PDGFB system is involved in the calcification of vascular smooth muscle cells (Diliberto et al., 1991. PubMed ID: 1905727).

SLC20A2 and XPR1 encode inorganic phosphate transporters (Wang et al., 2012. PubMed ID: 22327515; Legati et al., 2015. PubMed ID: 25938945).

Pathogenic variants in SLC20A2 account for about 41% of patients with idiopathic basal ganglia calcification (IBGC) (Hsu et al., 2013. PubMed ID: 23334463).

Pathogenic variants in PDGFB account for about 11% of patients with IBGC (Keller et al., 2013. PubMed ID: 23913003).

Pathogenic variants in PDGFRB account for about 10% of patients with IBGC (Nicolas et al., 2013. PubMed ID: 23255827).

Pathogenic variants in XPR1 account for about 4% of patients with IBGC (Legati et al., 2015. PubMed ID: 25938945).

Pathogenic large deletions in the SLC20A2 gene have been reported in about 16% of patients with IBGC who were previously found to be negative for pathogenic sequence variants in the SLC20A2, PDGFB, PDGFRB and XPR1 (David et al., 2016. 27245298).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).