Submission Details

The MAGED2 gene is located on the X chromosome at p11.21 and encodes melanoma antigen, family D, 2. MAGED2 regulates the expression, localization to the plasma membrane, and function of the sodium chloride cotransporters SLC12A1 (NKCC2) and SLC12A3 (NCC), both of which are critical components of renal salt reabsorption. MAGED2 was first reported in relation to X-linked recessive transient antenatal Bartter syndrome, type 5 in 2016 (Laghmani et al., PMID:27120771). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, transient antenatal Bartter syndrome, type 5 (OMIM:300971) and developmental delay (PMIDs: 27435318, 33504798). 22 variants (missense, in-frame indel, nonsense, frameshift, and large deletion) that have been reported in 26 probands in 4 publications (PMIDs: 27120771, 29146702, 29893154, 31302915) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by experimental evidence (expression studies and in vitro functional assays) (PMID: 27120771). MAGED2 was shown to be expressed in the thick ascending limb of the loop of Henle and in the distal tubules. Furthermore, MAGED2 promotes NKCC2 and NCC expression and activity. Finally, both p.Tyr346Ter and p.Arg446Cys were shown to functionally alter MAGED2 in patient cells and in vitro respectively. In summary, MAGED2 is definitively associated with X-linked recessive transient antenatal Bartter syndrome, type 5. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date March 17, 2022 (SOP Version 8).