Submission Details

The CASR gene is located on chromosome 3 at q13.33-q21.1and 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 evidence of differences in their inheritance pattern and phenotypic spectrum, with implications for clinical management. Therefore, the following disease entities have been split into multiple disease entities and curated separately: autosomal recessive hyperparathyroidism, neonatal (OMIM:239200), autosomal dominant hypocalciuric hypercalcemia, type I (OMIM:145980), and autosomal dominant hypocalcemia (OMIM:601198) lumped with Hypocalcemia, autosomal dominant, with Bartter syndrome (OMIM:601198). The preferred disease name suggested for this entity is ‘autosomal recessive neonatal hyperparathyroidism - CASR’.

CASR was first reported in relation to autosomal recessive neonatal hyperparathyroidism in 1993 (Pollak et al., PMID: 7916660). The mechanism of pathogenicity is predominantly reported to be loss of function. There have been isolated reports of monoallelic variants associated with neonatal hyperparathyroidism with a dominant negative mechanism of disease postulated (Pearce et al., PMID: 8675635). However, these are isolated case reports, a dominant-negative disease mechanism has not been proven, and a second causative variant in trans cannot be excluded. Therefore, our curation focuses exclusively on autosomal recessive neonatal hyperparathyroidism. Autosomal recessive neonatal hyperparathyroidism is characterised by severe neonatal hypercalcemia, elevated parathyroid hormone levels, enlargement of the parathyroid glands, failure to thrive and hyperparathyroid bone disease leading to multiple fractures, ribcage deformities and respiratory distress. This condition is usually fatal without parathyroidectomy early in life. At least 11 variants (3 missense, 2 nonsense, 3 frameshift, 2 canonical splice site, 1 complex insertional variant) have been reported in 10 probands in 10 publications (PMIDs: 7916660, 37246686, 7717399, 35380381, 34887979, 34111698, 30376845, 29354167, 24735972, 23817301) 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, in vitro assays in non-patient cells and expression studies. Homozygous Casr-/- mice had marked reduction in growth from day 2 of life, progressive lethargy and death at day 3 to 30 of life with elevated serum calcium, parathyroid hormone levels and significant hypocalciuria, recapitulating the human phenotype and supporting loss-of-function as a disease mechanism (Ho et al., PMID: 7493018). HEK-293 cells cultured and transfected with CASR variants reported in individuals with neonatal hyperparathyroidism showed an increase in EC50 set-point compared with wild-type cells (Pearce et al., PMID: 8878438). Human CaSR cDNA was able to be isolated from an adenomatous parathyroid gland and healthy parathyroid tissue. The cloned receptor when expressed in Xenopus oocytes responded to extracellular application of physiologically relevant concentrations of calcium and other calcium receptor agonists with the same rank order of potency compared with water-injected control oocytes. This demonstrates both expression of CaSR in parathyroid tissue and its biochemical function (Garrett et al., PMID:7759551). A total of 3/6 pts. for experimental evidence was reached.

In summary, there is definitive evidence supporting the relationship between CASR and autosomal recessive neonatal hyperparathyroidism. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.