Submission Details

The CNNM2 gene is located on chromosome 10 at q24.32 and encodes the cyclin and CBS domain divalent metal cation transport mediator 2. CNNM2 mediates transport of divalent metal cations, specifically Mg2+. It is expressed throughout the kidney, with specific expression in the thick ascending limb (TAL) of Henle's loop and the distal convoluted tubule (DCT). Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism or phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: renal hypomagnesemia 6 (OMIM:613882) and hypomagnesemia, seizures, and impaired intellectual development 1 (OMIM:616418). The preferred disease name suggested for this grouping of disorders is hypomagnesemia with or without seizures and intellectual disability. CNNM2 was first reported in relation to semi-dominant hypomagnesemia with or without seizures and intellectual disability in 2011 (Stuiver et al., PMID: 21397062). The mechanism of pathogenicity is known to be loss of function. Patients with this disorder present with hypomagnesemia, sometimes with variable seizures and/or intellectual disability among other syndromic disorders more frequently seen in more severe biallelic homozygous or compound heterozygous cases. Fourteen variants (missense, in-frame indel, nonsense, frameshift) have been reported in 14 probands in 4 publications (PMIDs: 21397062, 24699222, 30026055, 33600043 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by expression studies, in vitro assays in non-patient cells, and animal models. Immunohistochemistry on human kidney sections revealed that CNNM2 is expressed in both the TAL of Henle's loop, as indicated by and the DCT (PMID: 21397062). Additionally, where wildtype HEK293 cells showed increased Mg2+ uptake, HEK293 cells expressing mutated CNNM2 proteins did not, demonstrating a causative mechanism of hypomagnesemia (PMID: 24699222). Furthermore, knockdown of CNNM2 orthologues in zebrafish results in impaired development of the brain, abnormal neurodevelopmental phenotypes manifesting as altered locomotor and touch-evoke escape behaviours, and reduced body Mg content, indicative of impaired renal Mg2+ absorption (PMID: 24699222). Finally, homozygous and heterozygous Cnnm2 knock out mice presented with hypomagnesemia (PMID: 33600043). A total of 5/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between CNNM2 and semi-dominant hypomagnesemia with or without seizures and intellectual disability. 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 February 15, 2024 (SOP Version 10.1).