Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations

Area of Science:

• Genetics
• Hepatology
• Pediatric Nephrology

Background:

• Ductal plate malformations (DPM) encompass a range of conditions including Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD).
• The PKHD1 gene is primarily associated with ARPKD and CS, exhibiting significant inter- and intra-familial phenotypic variability.
• While rare familial cases of CD and exceptional associations with PKHD1 variants exist, the full spectrum of PKHD1-related phenotypes is still being elucidated.

Purpose of the Study:

• To investigate the genetic basis of DPM in a family with variable disease severity.
• To expand the known phenotypic spectrum associated with PKHD1 variants.
• To explore the role of PKHD1 in Caroli disease and other hepatic bile duct malformations.

Main Methods:

• Whole exome sequencing was performed on affected siblings.
• Segregation analysis of identified variants within the family.
• Review of additional familial DPM cases with PKHD1 variant analysis.

Main Results:

• Two compound heterozygous PKHD1 variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys) were identified in a family with DPM, segregating with symptoms.
• PKHD1 variants were also found in two other familial DPM cases, including one with CD.
• The findings indicate that PKHD1 variants can manifest as VMC and other hepatic bile duct malformations, with an inconstant renal phenotype in adults.

Conclusions:

• PKHD1 variants are associated with a broader spectrum of DPM than previously recognized, including VMC.
• Significant intra-familial phenotypic variability underscores the complexity of PKHD1-related disorders.
• PKHD1 may be a key gene in the pathogenesis of Caroli disease, and exome sequencing aids in expanding known genotype-phenotype correlations.