Introduction:
The porphyrin synthesis pathway consists of eight steps, and defects in any of these steps result in porphyric diseases, which are historically challenging to diagnose due to a wide diversity of symptoms. Given the overlap in symptoms, we identified a need for improvement in the gene-disease classifications for several of the genes involved in this pathway.

 

Methods:
We revised the MONDO nomenclature for porphyrin synthesis genes to a gene-first based naming system to increase specificity. Following ClinGen’s lumping and splitting criteria, we consolidated multiple disease entities linked to the same gene into a single entity to reflect the molecular evidence for a continuous disease spectrum. One gene, associated with distinct molecular mechanisms, was split into two disease entities. After lumping or splitting, inheritance pattern updates were necessary and completed in accordance with ClinGen guidelines.

Results:
Multiple disease entities associated with the genes HMBS, UROD, CPOX and PPOX were lumped into a single disease entity for each gene. We also updated the inheritance patterns for the newly created single disease entities to a semi-dominant inheritance pattern. The inheritance pattern updates were necessary since the previous autosomal dominant and autosomal recessive disease entities shared the same molecular mechanism. Heterozygotes present intermediate phenotypes, while patients with biallelic pathogenic variants have a more severe and earlier onset of disease. The gene, ALAS2, was split into two disease entities due to distinct gain-of-function and loss-of-function mechanisms, each associated with unique symptoms.

Conclusion:
Our revisions aim to update laboratory and clinical communication for porphyric disorders based on current genetic and clinical evidence. This will facilitate variant curation, allowing a single curation for variants that cause porphyric disease through either an autosomal dominant or autosomal recessive mode of inheritance.