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Common variants in the calcium sensing receptor gene (<jats:italic>CaSR<\/jats:italic>) have been associated with NL. Rare inactivating <jats:italic>CaSR<\/jats:italic> variants classically cause hyperparathyroidism, hypercalcemia and hypocalciuria. However, NL and familial hypercalciuria have been paradoxically associated with select inactivating <jats:italic>CaSR<\/jats:italic> variants in three kindreds from Europe and Australia.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To discover novel NL-associated <jats:italic>CaSR<\/jats:italic> variants from a geographically distinct cohort, 57 Pakistani families presenting with pediatric onset NL were recruited. The <jats:italic>CaSR<\/jats:italic> locus was analyzed by directed or exome sequencing.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We detected a heterozygous and likely pathogenic splice variant (GRCh37 Chr3:122000958A&gt;G; GRCh38 Chr3:12228211A&gt;G; NM_000388:c.1609-2A&gt;G) in <jats:italic>CaSR<\/jats:italic> in one family with recurrent calcium oxalate stones. This variant would be predicted to cause exon skipping and premature termination (p.Val537Metfs*49). Moreover, a splice variant of unknown significance in an alternative <jats:italic>CaSR<\/jats:italic> transcript (GRCh37 Chr3:122000929G&gt;C; GRCh38 Chr3:122282082G\u2009&gt;C NM_000388:c.1609-31G\u2009&gt;C NM_001178065:c.1609-1G\u2009&gt;C) was identified in two additional families.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Sequencing of the <jats:italic>CaSR<\/jats:italic> locus in Pakistani stone formers reveals a novel loss-of-function variant, expanding the connection between the <jats:italic>CaSR<\/jats:italic> locus and nephrolithiasis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12920-021-01116-5","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T11:03:08Z","timestamp":1636714988000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sequencing the CaSR locus in Pakistani stone formers reveals a novel loss-of-function variant atypically associated with nephrolithiasis"],"prefix":"10.1186","volume":"14","author":[{"given":"Ihsan","family":"Ullah","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Ottlewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wasim","family":"Shehzad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amjad","family":"Riaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadaqat","family":"Ijaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asad","family":"Tufail","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hafiza","family":"Ammara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shrikant","family":"Mane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirlee","family":"Shril","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedhelm","family":"Hildebrandt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Yasir","family":"Zahoor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amar J.","family":"Majmundar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"1116_CR1","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/j.eururo.2012.03.052","volume":"62","author":"CD Scales","year":"2012","unstructured":"Scales CD, Smith AC, Hanley JM, Saigal CS. 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Informed consent was obtained from all NL subjects at time of enrolment to obtain and report clinical data and pedigree information in publications.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"F.H. is a co-founder of Goldfinch Biopharma Inc. No other authors declare potential competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"266"}}