Therefore, discovery of novel NL-associated alleles can provide a deeper understanding of the role of CaSR in calcium handling and kidney stone disease. Nevertheless, these position-specific inactivating variants are exceedingly rare, given that a deleterious CaSR variant was not detected in a worldwide cohort of 697 NL families using gene panel or exome sequencing. These kindreds suggest that the functions of the calcium sensing receptor in serum calcium homeostasis and parathyroid hormone regulation can be uncoupled from its role in renal calcium excretion. NL has also been observed in three atypical kindreds from Europe and Australia with dominant inactivating variants (L650P, F881L, K336del), hypercalcemia, and familial hypercalciuria. 3.5% of cases with activating CaSR variants have NL or nephrocalcinosis, but this is typically an iatrogenic complication of treatment. NL is less typically the presenting problem in patients with calcium disorders caused by rare CaSR variants. NL has been associated with common CaSR variants, which cause either increased activity or decreased expression. Heterozygous activating CaSR variants cause autosomal dominant hypoparathyroidism, hypocalcemia and hypercalciuria (OMIM: 601198). Inactivating CaSR variants are associated with hyperparathyroidism, hypercalcemia, and hypocalciuria with dominant (OMIM: 145980) and recessive (OMIM: 239200) modes of inheritance. The calcium sensing receptor ( CaSR) gene regulates calcium homeostasis, and rare variants in CaSR cause calcium disorders. However, we demonstrated that a causative monogenic mutation can be detected in one of 30 known NL causing genes in ~ 6 to 11% of adult and ~ 17 to 29% pediatric cases. Formerly, monogenic causes of NL were thought to be restricted to rare tubulopathies and genetic syndromes. The causes of NL are not well understood. NL is associated with significant patient morbidity, recurrence, and healthcare costs. Nephrolithiasis (NL) affects 1 in 11 individuals during their lifetime. Sequencing of the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant, expanding the connection between the CaSR locus and nephrolithiasis. This variant would be predicted to cause exon skipping and premature termination (p.Val537Metfs*49). We detected a heterozygous and likely pathogenic splice variant (GRCh37 Chr3:122000958A>G GRCh38 Chr3:12228211A>G NM_000388:c.1609-2A>G) in CaSR in one family with recurrent calcium oxalate stones. The CaSR locus was analyzed by directed or exome sequencing. To discover novel NL-associated CaSR variants from a geographically distinct cohort, 57 Pakistani families presenting with pediatric onset NL were recruited. However, NL and familial hypercalciuria have been paradoxically associated with select inactivating CaSR variants in three kindreds from Europe and Australia. Rare inactivating CaSR variants classically cause hyperparathyroidism, hypercalcemia and hypocalciuria. Common variants in the calcium sensing receptor gene ( CaSR) have been associated with NL. Customers who currently have, or later purchase, a QIAGEN CLC Microbial Genomics Module Server Extension, could also be provided the Microbial Genomics Module under the same terms.Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant morbidity and cost.Customer with a QIAGEN CLC Genomics Server license agrees to act as the license administrator and distribute licenses to students.Registered users must be actively enrolled students, and registered for the course, subject to verification by QIAGEN and the sponsoring faculty member.Each educational license is limited to a 4-month subscription per course, or to the duration of the course (whichever is shorter).Registrants for the educational license to QIAGEN CLC Genomics Workbench Premium must hold an active QIAGEN CLC Genomics Server (master) license.Upon registration, licenses and direct download links will be provided to the professor/educator, who agrees to act as the 'educational training license administrator'. The student licenses can be issued repeatedly for the same educator, provided they are used for different courses.
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