PDGFB partial deletion: a new, rare mechanism causing brain calcification with leukoencephalopathy

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Idiopathic basal ganglia calcification (IBGC) is an autosomal dominant progressive neurological disorder.
• Mutations in SLC20A2, PDGFRB, and PDGFB are known causes of IBGC.
• Previous research identified point mutations and large deletions in SLC20A2, but copy number variants (CNVs) in these three genes remain understudied.

Observation:

• A novel quantitative PCR assay (QMPSF) was developed to detect CNVs in SLC20A2, PDGFRB, and PDGFB.
• In a cohort of 27 IBGC patients negative for point mutations in these genes, one patient presented a heterozygous partial deletion of PDGFB (exons 2-5).

Findings:

• The identified PDGFB deletion resulted in a transcript lacking critical functional domains, indicating a loss-of-function mechanism.
• The patient exhibited strio-pallido-dentate calcification, white matter hyperintensities, mood disorder, cognitive decline, and gait disturbance.

Implications:

• Intragenic deletion of PDGFB represents a new, rare cause of IBGC.
• Systematic screening for CNVs in known IBGC-associated genes is crucial for patients with unexplained disease.
• This finding expands the genetic landscape of IBGC and suggests a broader role for CNVs in the disorder.