The Porphyria Laboratory in the Biochemistry Department, St James’s Hospital, Dublin, has operated as a national service for porphyria in Ireland for over 40 years. During this time a comprehensive database integrating genetic, biochemical, and clinical data on more than 100 Irish kindreds affected by porphyria has been developed. This unique resource has been curated to facilitate the analysis of the genetic landscape of a range of porphyrias in Ireland. This analysis identified 87 families with a biochemically confirmed porphyria phenotype, among whom 74% had at least one member with a confirmed genetic diagnosis through Sanger sequencing-based variant. The primary presenting phenotypes included Acute Intermittent Porphyria (AIP, 27%), Erythropoietic Protoporphyria (EPP, 27%), Variegate Porphyria (VP, 20%), familial Porphyria Cutanea Tarda (fPCT, 11%), and Hereditary Coproporphyria (HCP, 10%). Correspondingly, the majority of genetic variants were found in the HMBS, FECH, PPOX, UROD and CPOX genes, with additional novel rare variants identified in ALAS1 and UROS. To aid in annotating and predicting the pathogenicity of identified variants, an in-house genetic reference database, PorphyriaDB, built on a cloud-native publicly-facing infrastructure (PorphyriaDB.com) has also been developed.

The findings highlight a heterogeneous genetic landscape of both acute and non-acute Porphyrias in Ireland, including the rare incidence of conditions such as XLP and CEP. Overall, an integrated molecular diagnostic service, underpinned by accurate variant annotation and interpretation, is critical in ensuring that genetic susceptibility to porphyrias is appropriately identified and monitored in affected families accordingly.