Submission Details

The ALAS2 gene was first reported in relation to X-linked erythropoietic protoporphyria in 2008, with the publication of eight affected families of diverse ancestries (PMID: 18760763). Affected individuals frequently present in early childhood with severe cutaneous photosensitivity and accumulation of protoporphyrin within erythrocytes, often with an elevated proportion of zinc-protoporphyrin. Decreased iron stores and abnormal transferrin saturation are observed in some patients, as are hyperbilirubinemia, elevated liver enzymes, and other signs of liver disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the molecular mechanism (gain-of-function) and mode of inheritance (X-linked dominant) were found to be distinct from patients with X-linked sideroblastic anemia 1, who instead harbor loss-of-function variants in ALAS2 and exhibit a stronger male predominance among affected patients. The phenotypic differences between the two groups of cases appear to represent separate disease entities rather than a spectrum of disease. Therefore, cases caused by inherited ALAS2 variants have been split into two separately-curated disease entities, referred to as X-linked erythropoietic protoporphyria (MONDO:0010420, MIM #300752), and X-linked sideroblastic anemia 1 (MONDO:0020721, MIM #300751).

Five suspected pathogenic variants have been scored as part of this curation (three frameshift and two nonsense), which have been collectively reported in thirteen probands in three publications (PMID: 18760763, PMID: 23263862, PMID: 23364466). All thirteen probands were heterozygous for their respective variants. Segregation evidence was available in one of these publications (PMID: 18760763) and has contributed to the scoring of the gene-disease relationship. This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level.

The mechanism of pathogenicity appears to be monoallelic gain-of-function, caused by frameshift or nonsense variants in the final exon (11) of ALAS2 that trigger disruption of the C-terminal autoinhibitory loop (PMID: 23263862). All probands in this curation harbored one variant allele within the ALAS2 locus.

This gene-disease association is also supported by experimental evidence, as ALAS2 encodes an enzyme responsible for synthesis of 5-aminolevulinic acid, a critical step in the protoporphyrin biosynthesis, heme biosynthesis, and cellular iron homeostasis pathways (PMID: 2347585, PMID: 26300302). ALAS2 expression is highly restricted to blood cells (PMID: 23715323) and erythrocytes specifically (PMID: 2347585). Elevated ALAS2 expression also occurs in the erythrocytes of patients with protoporphyria caused by loss-of-function variants in the FECH gene (PMID: 25179834). Finally, transgenic mice overexpressing Alas2 show related symptoms characterized as porphyria (PMID: 33785075).

In summary, ALAS2 is definitively associated with X-linked erythropoietic protoporphyria. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on March 11th, 2022 (SOP Version 8).