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Hypomagnesemia, seizures, and intellectual disability 1 (HOMGSMR1) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic or de novo heterozygous mutations in CNNM2 that disrupt magnesium homeostasis (PMID:24699222). Initial reports described five families with recessive CNNM2 variants presenting with severe hypomagnesemia, brain malformations, intellectual disability and seizures, establishing a key genetic link for this syndrome (PMID:24699222).
Subsequent cohort studies expanded the spectrum to 11 sporadic patients carrying heterozygous CNNM2 mutations, confirming loss-of-function effects in Mg2+ uptake assays and demonstrating decreased plasma membrane expression of mutant proteins (PMID:33600043). Additional de novo heterozygous missense variants were reported in individual cases presenting with refractory epilepsy or mild intellectual disability, sometimes in absence of overt hypomagnesemia (PMID:34490037; PMID:35846113; PMID:35806288). A 2024 analysis of seven novel heterozygous variants further underscored phenotypic variability, with some patients lacking neurological features despite pronounced renal Mg2+ wasting (PMID:38519529). Most recently, two unrelated families with novel p.Glu298del and p.Pro360Arg variants recapitulated the core HSMR phenotype and confirmed impaired CNNM2 membrane localization and Mg2+ efflux (PMID:40612795).
The CNNM2 variant spectrum encompasses missense changes (e.g., c.1079C>G (p.Pro360Arg)), frameshifts (e.g., c.274del (p.Ala92fs)) and nonsense alleles (e.g., c.12T>A (p.Cys4Ter)), as well as small in-frame deletions (e.g., p.Glu298del) detected in both homozygous and heterozygous states across diverse populations. No clear founder alleles have emerged, but recurrent CBS-domain mutations (e.g., p.Thr568Ile) highlight critical functional hotspots (PMID:25184538).
Functional characterization has integrated membrane topology mapping in kidney cells, revealing an extracellular N-terminus and intracellular C-terminus with glycosylation at Asn-112 enhancing surface stability (PMID:22399287), in vitro Mg2+ uptake assays confirming loss of transporter activity and TRPM7 regulation, and zebrafish cnnm2 knockdown models demonstrating neurodevelopmental rescue by wild-type but not mutant cRNA (PMID:24699222). Crystal structures of the CBS module have further shown that nucleotide binding and pathogenic mutations (e.g., T568I) induce conformational locking that may underlie defective Mg2+ sensing (PMID:25184538).
Collectively, clinical, genetic and experimental data support a Strong gene–disease association: over 21 independent probands, segregation in seven families, and concordant functional evidence demonstrating a loss-of-function mechanism. No credible conflicting evidence has emerged to date. Additional reports continue to refine genotype-phenotype correlations and may exceed current ClinGen scoring maxima.
Key Take-home: CNNM2 mutation testing enables diagnosis of HOMGSMR1 in patients with hypomagnesemia, seizures, and intellectual disability and guides genetic counseling and potential Mg2+ supplementation strategies.
Gene–Disease AssociationStrong21 probands across 7 families, multi-family segregation and concordant functional data Genetic EvidenceStrong21 probands with recessive and de novo variants, heterogeneous variant classes reaching genetic cap Functional EvidenceModerateMultiple in vitro topology, stability and Mg2+ transport assays, zebrafish knockdown and rescue models demonstrate loss-of-function |