Delineating the Genetic Basis of RNF213-related vasculopathies: The association of PKHD1 variants with bilateral...

Area of Science:

• Genetics
• Neurology
• Vascular Biology

Background:

• Moyamoya disease (MMD) is a rare cerebrovascular disorder marked by progressive stenosis of major intracranial arteries.
• While RNF213 is a known susceptibility factor, the genetic underpinnings of MMD phenotypes remain incompletely understood.
• Investigating additional genetic factors is crucial for understanding MMD's diverse clinical manifestations.

Purpose of the Study:

• To identify novel genetic factors associated with Moyamoya disease (MMD) beyond the RNF213 gene.
• To explore genetic contributions to differential disease phenotypes, specifically bilateral MMD, unilateral MMD, and intracranial artery stenosis (ICAS).
• To investigate the role of the PKHD1 gene in the pathogenesis of bilateral MMD.

Main Methods:

• Whole-exome sequencing was performed on 122 patients with Moyamoya disease (MMD) or intracranial artery stenosis (ICAS) and 458 healthy controls.
• Case-control and in-case association analyses were conducted using single-variant and gene-based testing.
• Expression analysis of Pkhd1 in mouse cerebrovascular cells was performed using publicly available single-cell transcriptome data.

Main Results:

• No significant genetic locus was identified in the initial case-control analysis.
• The PKHD1 gene emerged as a top candidate in the in-case analysis, particularly associated with bilateral MMD.
• Two rare, damaging variants in PKHD1 (p.Ile2364Asn and p.Ser3210Cys) were significantly more prevalent in bilateral MMD patients and validated in an independent cohort.
• Pkhd1 expression was found to be elevated in specific endothelial cell populations in mouse cerebrovasculature.

Conclusions:

• The PKHD1 gene is implicated as a potential novel susceptibility factor for bilateral Moyamoya disease (MMD).
• Specific rare variants in PKHD1 may contribute to the development of bilateral MMD.
• Further research into endothelial gene expression, particularly involving PKHD1, is warranted in patients with RNF213 and PKHD1 mutations.