Submission Details

Autosomal dominant

08/27/2019

The CNNM2 gene is located on chromosome 10 at 10q24.32 and encodes the cyclin and CBS domain divalent metal cation transport mediator 2 protein. This protein shows high basolateral expression in the renal tubule segments most involved in magnesium resorption and is also expressed in the brain (21397062: Stuiver et al. 2011). Functional studies suggest it acts to regulate magnesium transport (21397062: Stuiver et al. 2011; 24699222: Arjona et al. 2014). CNNM2 was first reported in relation to CNNM2-related hypomagnesemia, seizures and intellectual disability, autosomal dominant, in 2011 (21397062: Stuiver et al. 2011). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least five probands in two publications (21397062: Stuiver et al. 2011; 24699222: Arjona et al. 2014). Three cases carried CNNM2 variants in a heterozygous state, variants occurred de novo in three of these cases. Of the five unique variants, four were missense and one resulted in a frameshift variant and predicted loss of function. Evaluation of the missense variants in vitro indicates a loss of function or hypomorphic mechanism of disease. This gene-disease relationship is supported by experimental data including a zebrafish, CNNM2 morpholino knockdown model which recapitulated the key features of disease, demonstrating a gene dosage dependant reduction in magnesium levels, brain malformation, and signs of neuromuscular impairment. These phenotypes were exacerbated by expression of mutant CNNM2 and rescued by expression of wildtype CNNM2 (24699222: Arjona et al. 2014). Additional experimental support comes from expression studies and in vitro functional assays (21397062: Stuiver et al. 2011; 24699222: Arjona et al. 2014). In summary, there is strong evidence to support the relationship between CNNM2 and autosomal dominant CNNM2-related hypomagnesemia, seizures and intellectual disability. Additional clinical reports are needed to reach a definitive classification.

24699222 21397062