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Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 nonmalformed controls. Our findings indicated that rare, protein\u2010altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss\u2010of\u2010function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (\n                    <jats:italic>p<\/jats:italic>\n                    = 0.01). Second, in gene\u2010level analyses, the burden of rare alleles showed greater case\u2010association for several genes previously implicated in cleft risk. For example,\n                    <jats:italic>BHMT<\/jats:italic>\n                    displayed a 10\u2010fold increase in protein\u2010altering variants in CLP cases (\n                    <jats:italic>p<\/jats:italic>\n                    = .03), including multiple case occurrences of a rare frameshift mutation (K400\u2009fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (\n                    <jats:italic>WNT9B<\/jats:italic>\n                    ,\n                    <jats:italic>BMP4<\/jats:italic>\n                    ,\n                    <jats:italic>BMPR1B<\/jats:italic>\n                    ) as well as the methionine cycle (\n                    <jats:italic>MTRR<\/jats:italic>\n                    ). We conclude that rare coding variants may confer risk for isolated CLP.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.61183","type":"journal-article","created":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T09:06:48Z","timestamp":1557220008000},"page":"1260-1269","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8782-2573","authenticated-orcid":false,"given":"Nicholas J.","family":"Marini","sequence":"first","affiliation":[{"name":"California Institute for Quantitative Biosciences, Department of Molecular and Cellular Biology University of California  Berkeley California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kripa","family":"Asrani","sequence":"additional","affiliation":[{"name":"California Institute for Quantitative Biosciences, Department of Molecular and Cellular Biology University of California  Berkeley California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Stanford University School of Medicine  Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasper","family":"Rine","sequence":"additional","affiliation":[{"name":"California Institute for Quantitative Biosciences, Department of Molecular and Cellular Biology University of California  Berkeley California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7438-4914","authenticated-orcid":false,"given":"Gary M.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Stanford University School of Medicine  Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23244"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004479"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02721-0"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21972"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.9503.1"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.580"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.333"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20740"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20376"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0109038"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3016.1991.tb00728.x"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2933"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.3109\/02844316709006555"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2009.06.020"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/SCS.0000000000004488"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36912"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23320"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.07.007"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12038-013-9298-7"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38210"},{"key":"e_1_2_7_23_1","first-page":"2862","article-title":"A multi\u2010ethnic genome\u2010wide association study identifies novel loci for non\u2010syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13","volume":"25","author":"Leslie E. 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