PIH1D2 Loss-of-Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia.
Alina Kurolap, Chofit Chai Gadot, Adel Shalata et al.
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Case in brief
Two unrelated patients with left isomerism heterotaxy were found by genome sequencing to have biallelic loss-of-function variants in PIH1D2. In patient-derived fibroblasts, RNA analyses confirmed abnormal splicing, and PIH1D2 expression was absent in cells from one patient. The cells showed impaired cell-cycle re-entry and S-phase progression, as well as reduced primary ciliogenesis; overexpression of wild-type PIH1D2 partially rescued cell-cycle defects. Biliary atresia was present in one patient. The findings support PIH1D2 as a disease gene for left isomerism and link its loss to cellular defects relevant to development.
What made this case unusual
The report links biallelic PIH1D2 loss of function—previously unassociated with human disease—to left isomerism heterotaxy, with biliary atresia in one of the two patients.
Diagnostic / clinical pearl
In left isomerism heterotaxy, PIH1D2 loss-of-function variants may be relevant; patient-cell studies in this report connected the variants with impaired ciliogenesis and cell-cycle progression.
Why it matters
The findings broaden the genetic and mechanistic spectrum of cilia-related laterality disorders and raise a possible connection between PIH1D2-related developmental defects and biliary disease.