Erythropoietic protoporphyria, mild variant

Gene: ALAS2

Comment on list classification: Pathogenic variants reported in OMIM/ClinVar, and described as a recent discovery by the reviewer - two publications with multiple cases, with functional data supporting a gain-of-function mechanism.

Created: 29 Jan 2016, 3:40 p.m.

Comment on mode of pathogenicity: Gain of function - see Reviewer's comments and the publications.

Created: 29 Jan 2016, 3:31 p.m.

Described as "X-linked dominant" on expert list. Confirmed on OMIM.

Created: 29 Jan 2016, 3:23 p.m.

Transcript and phenotypes under "gene summary" were accidently copied over to the review on Nov 12th 2015 and were not provided by the reviewer.

Created: 12 Nov 2015, 1:43 p.m.

Green List (high evidence)

ALAS2 is a more recent discovery and a few cases of X-linked EPP have been reported _ mostly in males with females often asymptomatic or with minor scars in sun-exposed sites. Most mutations are small deletions or nonsense mutations near C-terminus which lead to increased enzyme activity (gain-of-function). Mutations in ALAS2 account for 2-5% of total cases in Europe (but up to 10% in North America). Mutations in ALAS2 may be under-recognised to date, but current data indicate that, taken together, mutations in FECH and ALAS2 account for ~94% of total EPP cases, i.e. further genetic heterogeneity is suspected in ~6% of cases.

Created: 12 Nov 2015, 1:34 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Anemia, sideroblastic, X-linked, 300751Protoporphyria, erythropoietic, X-linked, 300752

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments