PIH1D2 Loss-of-Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia

PIH1D2

Biallelic loss-of-function PIH1D2 variants (aberrant splicing, loss of expression) impairing primary ciliogenesis and cell cycle progression

In two unrelated patients with left isomerism heterotaxy, genome sequencing identified biallelic loss-of-function variants in PIH1D2, a gene not previously associated with human disease. Transcript analyses confirmed aberrant splicing, and immunofluorescence showed loss of PIH1D2 expression in Patient 1's fibroblasts. RNA-seq revealed dysregulation of cell cycle and developmental signalling pathways; patient fibroblasts showed impaired cell cycle re-entry from G0, reduced S-phase progression and significantly reduced primary ciliogenesis. Wild-type PIH1D2 overexpression partially rescued these defects, and one of the two patients had biliary atresia.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A new laterality disorder gene, already captured by exome and genome sequencing, with a consistent functional body of evidence (splicing, cell cycle, ciliogenesis, partial rescue). Only two patients: the gene-disease relationship needs consolidation in other families, especially as biliary atresia was seen in only one of them. The gene is worth keeping in mind when interpreting unsolved heterotaxy.

Analysis by Dr Thibaut Benquey