Updates to gene-disease classifications and inheritance patterns for porphyrias.

Area of Science:

• Biochemistry
• Genetics
• Medical Diagnostics

Background:

• Porphyrias are a group of genetic disorders caused by pathogenic variants in heme synthesis pathway genes.
• Delayed diagnosis of porphyrias is common due to nonspecific and episodic symptoms.
• Accurate genetic diagnostics are crucial for timely porphyria management.

Purpose of the Study:

• To perform comprehensive gene-disease curations for all genes in the heme synthesis pathway.
• To address challenges in porphyria diagnosis stemming from variable inheritance patterns and overlapping variants.
• To establish improved nomenclature for gene-disease relationships in porphyrias.

Main Methods:

• Expert panel review and gene-disease curation for the eight enzyme-catalyzed steps of the heme synthesis pathway.
• Consolidation of distinct disease assertions (e.g., dominant vs. recessive) into single gene-disease entries.
• Development of novel, gene-based parent terms encompassing monoallelic and biallelic subtypes.

Main Results:

• Several heme synthesis genes (HMBS, UROD, CPOX, PPOX) exhibited multiple disease assertions, often differing by inheritance pattern.
• A unified approach ('lumping') was adopted for gene-disease curations, integrating patients from different disease subtypes.
• A semidominant inheritance pattern was assigned to parent terms to reflect overlapping variants and allele dosage effects on phenotypic severity.

Conclusions:

• The developed gene-disease curations for the heme synthesis pathway enhance downstream variant curation accuracy.
• This work provides a foundation for improved molecular diagnostic reporting of porphyrias.
• Clarified nomenclature facilitates precise variant interpretation and reporting in heme synthesis disorders.