Submission Details

The CASR gene is associated in the literature with disorders of calcium homeostasis, including autosomal dominant hypocalcemia (ADH), autosomal dominant familial (benign) hypocalciuric hypercalcemia (FHH), and autosomal recessive neonatal severe primary hyperparathyroidism (NSHPT). Although individuals with hypocalcemia due to ADH may experience hypocalcemic seizures, the disorders of calcium homeostasis do not cause primary epilepsy. However, in 2008 CASR was reported in association with autosomal dominant epilepsy in the absence of any abnormalities of calcium homeostasis (Kapoor et al., PMID: 18756473). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism(s) and phenotypic variability for these disorders. Therefore, epilepsy is curated separately from the disorders of calcium homeostasis, which are not considered in this curation. The Kapoor et al., publication (PMID: 18756473) included a large family reported to have idiopathic generalized epilepsy (IGE) with eight affected family members who had juvenile myoclonic epilepsy (JME), nocturnal myoclonic seizures, febrile convulsions, generalized tonic-clonic seizures (GTCS), and/or complex partial seizures who had linkage to the region on chromosome 3q13.3-q21.1 where the CASR gene is located. There were 74 disease-associated genes noted to be within the critical region but only 13 genes were selected for candidate gene sequencing based on known or suspected expression in the central nervous system. The CASR variant c.2693G>A (p.Arg898Gln) was identified in all affected individuals in the family and no unaffected individuals, but it is also present in gnomAD with a minor allele frequency of 0.0262% (8/30586 alleles) in the South Asian population, which is higher than expected given the prevalence of JME. The Kapoor publication also tested 90 unrelated individuals reported to have JME, and four additional missense variants were identified in five probands. However, limited clinical and family history information is provided for these individuals, no segregation analysis was performed, no other epilepsy genes were tested to evaluate for other possible explanations for the phenotype, and several of the variants have a minor allele frequency in gnomAD that is higher than expected based on the prevalence of JME in the population. A more recent publication (PMID: 31763346) reported a proband with a history of hypocalcemia and seizures who had a missense variant in CASR that has been published in other individuals with ADH. However, the proband was also reported to have intractable childhood-onset seizures including eyelid myoclonus with absences, intellectual disability, and behavioral issues that were attributed by the authors to the CASR variant. However, an epilepsy gene panel or exome/genome sequencing were not performed to evaluate for other possible causes of epilepsy, so it is unclear whether the CASR variant is the cause of the other neurodevelopmental features. There is currently no functional data that supports an association between CASR and primary epilepsy. Expression analysis in fetal mice has indicated there is significant CaSR expression in the superior cervical ganglion (SCG), a population of sympathetic neurons (PMID: 18223649). Additionally, altered calcium concentration were noted to impact neurite growth in vitro in developing neurons. However, confirmation of expression in the central nervous system is not sufficient evidence to support an association with epilepsy. In summary, the evidence supporting the relationship between CASR and autosomal dominant epilepsy has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role CASR plays in this disease. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on the meeting date 03/02/2021 (SOP Version [8]).