Updates to gene-disease classifications and inheritance patterns for porphyrias

The heme synthesis pathway consists of eight enzyme-catalyzed steps, and pathogenic variants in the genes encoding these enzymes cause porphyrias. Diagnosis of certain porphyrias is often significantly delayed, due to their episodic and nonspecific symptoms that mimic more common conditions. To improve genetic diagnostics, which are increasingly used as a first-line approach, the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel identified the need to perform gene-disease curations for all genes in this pathway. During this process, we found that several genes (HMBS, UROD, CPOX, and PPOX) had multiple disease assertions, primarily differentiated by dominant versus recessive inheritance. For example, deficiency of HMBS is associated with both autosomal dominant acute intermittent porphyria (AIP) and autosomal recessive homozygous dominant AIP (HD-AIP). Yet, both conditions result from loss-of-function of the HMBS protein, and some recessive cases share identical causative variants with dominant cases. Therefore, our expert panel decided to include patients from both disease assertions (AIP and HD-AIP) as part of a single gene-disease curation rather than separating these groups of patients. This approach correctly links the variable affecting severity to allele dosage. This "lumping" process also required novel parent terms that encompass all disease subtypes and have gene-based nomenclature. Parent terms incorporating both monoallelic and biallelic subtypes were assigned a semidominant inheritance pattern, reflecting the overlapping variants and variable phenotypic severity based on residual enzyme activity. These gene-disease curations for the heme synthesis pathway pave the way for improved downstream variant curation which is a critical requirement to improve porphyria diagnostics. A key focus of this undertaking is to clarify and advance more appropriate nomenclature for these gene-disease relationships, enabling molecular laboratories to report variants in the heme synthesis pathway with greater precision.