The CASR gene is located on chromosome 3 at q13.33-q21.1 and encodes the calcium-sensing receptor that determines extracellular calcium concentration and is predominantly expressed in PTH-producing chief cells of the parathyroid gland and the cortical thick ascending limb of the kidney tubule. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in the molecular mechanisms, inheritance pattern and phenotypic spectrum for Hypocalcemia, autosomal dominant (OMIM:601198) and Hypocalcemia, autosomal dominant, with Bartter syndrome (OMIM:601198). Therefore, these disease entities have been lumped into one disease entity, with the preferred disease name suggested for this disorder being ‘autosomal dominant hypocalcemia - CASR’. Autosomal recessive neonatal hyperparathyroidism (OMIM:239200) and autosomal dominant hypocalciuric hypercalcemia, type 1 (OMIM:145980) have been curated separately.
The CASR gene was first reported in relation to autosomal dominant hypocalcemia in 1996 (Baron et al., PMID: 8733126). The mechanism of pathogenicity is shown to be gain of function. This condition is characterised by hypoparathyroidism, hypocalcemia, hyperphosphatemia due to inadequate secretion of parathyroid hormone and increased urinary calcium excretion. At least 35 missense variants have been reported in 35 probands in 13 publications [PMIDs: 8813042, 22422767, 12191970, 9253358, 35818129, 35402765, 29743878, 25766501, 19915295, 12107202, 14677060, 8733126, 33506158] and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level and segregation data. This gene-disease relationship is also supported by animal models. PMID:15347804 showed that 'Nuf' founder mouse models with the heterozygous gain of function CASR Leu723Gln variant recapitulated the human phenotype, with transient expression of wild-type and mutant CaSRs in HEK-293 transfected cells showing significantly lower EC50. A total of 2/6 pts. for experimental evidence was reached.
In summary, there is definitive evidence supporting the relationship between CASR and autosomal dominant hypocalcemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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