Molecular characteristics

HSMR syndrome is caused by mutations in the CNNM2 gene (location 10q24.32). Mutations in CNNM2 include nonsense variants, missense mutations, and frame shift mutations. Different mutations in the CNNM2 gene have been found by exome sequencing and Sanger sequencing. The majority of patients have been affected by heterozygous mutations, either by de novo or inherited in an autosomal dominant fashion. Only two cases to date have been reported with recessive mutations, which have been associated with brain malformations. The role of CNNM2 in brain development and functioning is yet to be elucidated.