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CNNM2  (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD). We identified two new cases with  CNNM2  novel  de novo  pathogenic variants, c.814T>C and c.976G>C. They both presented with infantile-onset epilepsy with DD and hypomagnesemia refractory to magnesium supplementation. To date, 21 cases with  CNNM2 -related disorders have been reported. We combined all 23 cases to analyze the features of  CNNM2 -related disorders. The phenotypes can be classified into three types: type 1, autosomal dominant (AD) inherited simple hypomagnesemia; type 2, AD inherited hypomagnesemia with epilepsy and ID/DD; and type 3, autosomal recessive (AR) inherited hypomagnesemia with epilepsy and ID/DD. All five type 1 cases had no epilepsy or ID/DD; they all had hypomagnesemia, and three of them presented with symptoms secondary to hypomagnesemia. Fifteen type 2 patients could have ID/DD and seizures, which can be controlled with antiseizure medications (ASMs); their variations clustered in the DUF21 domain of CNNM2. All three type 3 patients had seizures from 1 to 6 days after birth; the seizures were refractory, and 1/3 had status epilepticus; ID/DD in these AR-inherited cases was more severe than that of AD-inherited cases; they all had abnormalities of brain magnetic resonance imaging (MRI). Except for one patient whose serum magnesium was the lower limit of normal, others had definite hypomagnesemia. Hypomagnesemia could be improved after magnesium supplement but could not return to the normal level. Variations in the CBS2 domain may be related to lower serum magnesium. However, there was no significant difference in the level of serum magnesium among the patients with three different types of  CNNM2 -related disorders. The severity of different phenotypes was therefore not explained by decreased serum magnesium. We expanded the spectrum of  CNNM2  variants and classified the phenotypes of  CNNM2 -related disorders into three types. We found that DUF21 domain variations were most associated with  CNNM2 -related central nervous system phenotypes, whereas hypomagnesemia was more pronounced in patients with CBS2 domain variations, and AR-inherited  CNNM2 -related disorders had the most severe phenotype. These results provide important clues for further functional studies of  CNNM2  and provide basic foundations for more accurate genetic counseling.

CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance