Executive Summary SLC11A2:
SLC11A2, anemia, hypochromic microcytic with iron overload (MONDO:0000104), autosomal recessive
SLC11A2 was first described as an anemia, hypochromic microcytic, with iron overload 1-causing gene in 2005 (PMID: 15459009, Mims et al. 2005). The specific disease entity, Anemia, hypochromic microcytic, with iron overload 1 (MONDO:0000104, OMIM:600523), is one of at least two known forms of microcytic hypochromic anemia and twenty known forms of microcytic anemia. Some of the most common patient phenotypes are: Hypochromic microcytic anemia, Increased circulating iron concentration, Anemia, Elevated transferrin saturation, Elevated hepatic iron concentration, Microcytic anemia, Increased circulating ferritin concentration, Pallor, Decreased circulating ferritin concentration, Decreased mean corpuscular hemoglobin concentration, Reticulocytosis, Hypochromia.
Twelve variants: (Missense (9), Splice Site (2) & Multi_Frame Deletion (1)) that have been reported in 9 probands in 8 publications (PMIDs: 16439678, 16160008, 15459009, 35457224, 21871825, 19553145, 23016933 and 29178181) are included in this curation.
Many of the probands were diagnosed during childhood after experiencing symptoms including Hypochromic microcytic anemia, Increased circulating iron concentration, Anemia, Elevated transferrin saturation, Elevated hepatic iron concentration and Microcytic anemia. Family history tended to be unremarkable. Siblings of the probands were generally found to be unaffected although there were instances of asymptomatic carrier siblings, a brother who had a haematological phenotype similar to one of the probands and a previous sibling to a proband that died intrauterine at week 39 presenting cardiomegaly and fetal ascites.
Overall, the mechanism of pathogenicity appears to be loss of function as shown in the probands.
This gene-disease relationship is also supported by multiple forms of experimental evidence such as Model System: Mouse (Mus musculus) (Quantity: 1), Model System: Rat (Rattus norvegicus domestica) (Quantity: 1), BioChem B (Quantity: 1), (PMIDs: 15849611, 24795636 and 9448300). First, a mouse model that has anemia and elevated hepatic iron concentration recapitulates the anemia and elevated hepatic iron concentration found in the human probands (Gunshin et al. 2015, PMID: 15849611). Then, Veuthey et al. 2014 captured a rat model with the phenotypes of microcytosis, anisocytosis and poikilocytosis that recapitulates the phenotypes found in the human probands (PMID: 24795636). Lastly, Fleming et al. 1998 (PMID: 9448300) describes an experiment where the expressing wild-type SLC11A2 gives HEK293T cells the ability to transport iron.
In conclusion, SLC11A2 is definitively associated with anemia, hypochromic microcytic, with iron overload 1-causing gene. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time.
This classification was approved by the General IEM GCEP on April 25th, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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