Primary brain calcification: an international study reporting novel variants and associated phenotypes

Area of Science:

• Genetics
• Neurology
• Rare Diseases

Background:

• Primary familial brain calcification (PFBC) is a rare, inherited disorder affecting cerebral microvasculature.
• PFBC presents with diverse motor, cognitive, and neuropsychiatric symptoms.
• Autosomal-dominant inheritance is typical, with four known causative genes: SLC20A2, PDGFRB, PDGFB, and XPR1.

Purpose of the Study:

• To screen the coding regions of four primary brain calcification genes (SLC20A2, PDGFRB, PDGFB, XPR1) in 177 unrelated probands.
• To identify and classify sequence variants according to ACMG-AMP recommendations.
• To correlate genetic findings with clinical manifestations in PFBC patients.

Main Methods:

• Genetic screening of SLC20A2, PDGFRB, PDGFB, and XPR1 coding regions in 177 probands.
• Classification of sequence variants as pathogenic, likely pathogenic, or variants of uncertain significance (VUS).
• Clinical data analysis to assess symptom spectrum and age of onset in variant carriers.

Main Results:

• Pathogenic or likely pathogenic variants were found in 19.2% of probands, and VUS in 6.2%.
• SLC20A2 variants were most frequent (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%).
• 81.5% of carriers were symptomatic, with parkinsonism, cognitive impairment, and psychiatric disturbances being most common.

Conclusions:

• Genetic variants in SLC20A2, XPR1, PDGFB, and PDGFRB are significant contributors to primary familial brain calcification.
• Identified pathogenic/likely pathogenic variants are valuable for genetic counseling.
• Further evidence is needed to classify VUS in PFBC patients.