Background: Mutation screening of the CASR by DNA sequencing is commonly used in the diagnosis of disorders of calcium metabolism, such as familial hypocalciuric hypercalcaemia (FHH). Exon copy number variation is not detected by currently used molecular genetic screening methods, and might be a genetic cause of inherited forms of hyper- or hypocalcaemia caused by the CASR.
Objective: We wanted to further evaluate possible genetic causes for disorders of calcium metabolism, by investigating the prevalence of exon copy number variations, such as large deletions or duplications of the CASR.
Patients and methods: The study included 257 patient samples referred to our laboratory for molecular genetic analysis of the CASR gene. A total of 245 were patients suspected to have FHH, while the remaining 12 samples represent patients with a phenotype of idiopathic hypocalcaemia/hypoparathyroidism. All samples were previously found negative for CASR mutations. Multiplex ligation-dependent probe amplification was used to screen the patients for exon copy number variations.
Results: All exons were amplified with mean normalised ratios between 0.98 and 1.06. We did not identify any exon copy number variation in the CASR. Bioinformatic analyses revealed that the CASR gene contains 52% repeated elements, of which approximately 6% consist of Alu elements.
Conclusions: The present study indicates that including CASR MLPA analysis as a routine part of the diagnostic setup is not necessary, but could still be of interest in cases with a clear family history and no evidence of missense mutations in the CASR gene.