FIGURE 3.

Literature review of hypomagnesemia, seizures, and mental retardation (HSMR) syndrome caused by a CNNM2 gene mutation. (a) According to the phenotypic analysis of 24 reported HSMR cases, we found that in addition to the known triad (hypomagnesemia, seizures, and mental retardation), other high‐frequency phenotypes include language retardation, motor development disorder, and obesity. Furthermore, a few patients will have atrial septal defect (ASD), microcephaly, and other phenotypes. CNNM2 gene mutations causing HSMR are mainly de novo, followed by both dominant and recessive inheritance patterns. The main type of variation found in the literature review was missense mutations. Nonsense mutation, frameshift mutation, and copy number variations (CNVs) were also reported. (b) The protein encoded by CNNM2 contains an N‐terminal extracellular domain, four transmembrane α‐helix transmembrane domains, cystathionine β‐synthase (CBS‐par) domain, and the cyclic nucleotide binding homology (CNBH) domain. Homozygous mutation of key amino acids or domains of proteins may lead to more serious clinical manifestations. For example, the homozygous mutation adjacent to Asn112 can lead to a severe nervous system phenotype (Arjona et al., 2014). A missense mutation of the CBS2 domain can also lead to a severe nervous system phenotype and even death (Accogli et al., 2019). Red indicates severe phenotype, black indicates reported loci, and green indicates variant loci of our patient