# Prenatal Recurrence of Ductal Plate Malformations Leads to PKHD1 Variant Reclassification

## TL;DR

This study shows how recurring liver abnormalities in two pregnancies helped reclassify a genetic variant as harmful, improving understanding of a liver disease gene.

## Contribution

The study demonstrates how variant reclassification can occur through prenatal recurrence and multi-modal analysis.

## Key findings

- A PKHD1 variant (c.533T>A) was reclassified as likely pathogenic due to recurrence in two pregnancies.
- Combining prenatal imaging, postmortem exams, and gene sequencing improved variant classification.
- The findings expand the known clinical effects of PKHD1-related disorders.

## Abstract

Ductal plate malformations (DPM) encompass a spectrum of congenital liver disorders characterized by abnormal bile duct development, often associated with conditions such as Caroli disease. Variants in the PKHD1 gene cause a wide spectrum of DPM, but genotype–phenotype correlations remain challenging. We report a couple with two consecutive terminated pregnancies following prenatal detection of hepatic anomalies suggestive of DPM. Genetic analyses revealed compound heterozygous variants in PKHD1 in both fetuses. One variant (c.931A>G) was classified as likely pathogenic, while the second (c.533T>A), initially reported as a variant of uncertain significance, was reclassified as likely pathogenic after recurrence of the phenotype. This case highlights the importance of integrating prenatal imaging, postmortem examination, and whole‐gene sequencing to refine variant classification and improve genetic counseling. Furthermore, it expands the clinical spectrum of PKHD1‐related disorders.

What's already known about this topic?◦Ductal plate malformations (DPM) encompass a spectrum of congenital liver disorders characterized by abnormal bile duct development, often linked to conditions such as Caroli disease.◦Variants in the PKHD1 gene cause a wide spectrum of ductal plate malformations◦Prenatal imaging can detect features of DPM; however, genotype–phenotype correlations remain challenging due to limited evidence for many genetic variants.What does this study add?◦This study documents a case of two consecutive pregnancies with recurrent DPM, which led to the reclassification of a PKHD1 variant (c.533T>A) from uncertain significance to likely pathogenic.◦It underscores the importance of integrating prenatal imaging, postmortem examination and whole gene sequencing to refine variant classification and enhance genetic counseling.◦Moreover, it expands the clinical spectrum of PKHD1‐related disorders

What's already known about this topic?

Ductal plate malformations (DPM) encompass a spectrum of congenital liver disorders characterized by abnormal bile duct development, often linked to conditions such as Caroli disease.

Variants in the PKHD1 gene cause a wide spectrum of ductal plate malformations

Prenatal imaging can detect features of DPM; however, genotype–phenotype correlations remain challenging due to limited evidence for many genetic variants.

What does this study add?

This study documents a case of two consecutive pregnancies with recurrent DPM, which led to the reclassification of a PKHD1 variant (c.533T>A) from uncertain significance to likely pathogenic.

It underscores the importance of integrating prenatal imaging, postmortem examination and whole gene sequencing to refine variant classification and enhance genetic counseling.

Moreover, it expands the clinical spectrum of PKHD1‐related disorders