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In total, 51 simplex cases were included to test the hypothesis of <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content> as a mendelian trait caused by either heterozygous autosomal dominant or bi\u2010allelic autosomal recessive pathogenic variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The cohort was whole exome sequenced (<jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>) at 100\u00d7 coverage. Both a dominant\u2010 and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young\u2010onset <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content> cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss\u2010of\u2010function) or allele frequency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified one pathogenic variant in <jats:italic><jats:styled-content style=\"fixed-case\">PTEN<\/jats:styled-content><\/jats:italic> in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in <jats:italic><jats:styled-content style=\"fixed-case\">PMS<\/jats:styled-content>2<\/jats:italic> that was originally not identified by <jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content> due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes (<jats:italic><jats:styled-content style=\"fixed-case\">BMPR<\/jats:styled-content>1A<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">BRIP<\/jats:styled-content>1<\/jats:italic>, and <jats:italic><jats:styled-content style=\"fixed-case\">SRC<\/jats:styled-content>)<\/jats:italic>, three truncating variants in possibly novel cancer genes (<jats:italic><jats:styled-content style=\"fixed-case\">CLSPN<\/jats:styled-content><\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">SEC<\/jats:styled-content>24B<jats:bold>, <\/jats:bold><jats:styled-content style=\"fixed-case\">SSH<\/jats:styled-content>2<\/jats:italic>) and four candidate missense variants in <jats:italic><jats:styled-content style=\"fixed-case\">ACACA<\/jats:styled-content><jats:bold>, <\/jats:bold><jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>2C2<jats:bold>, <\/jats:bold><jats:styled-content style=\"fixed-case\">INPP<\/jats:styled-content>4A,<\/jats:italic> and <jats:italic><jats:styled-content style=\"fixed-case\">DIDO<\/jats:styled-content>1<jats:bold>.<\/jats:bold><\/jats:italic> We also identify five possible autosomal recessive candidate genes: <jats:italic><jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>10B<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">PKHD<\/jats:styled-content>1<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">UGGT<\/jats:styled-content>2<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">MYH<\/jats:styled-content>13<\/jats:italic>,<jats:italic> <jats:styled-content style=\"fixed-case\">TFF<\/jats:styled-content>3<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Two clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with <jats:styled-content style=\"fixed-case\">CRC<\/jats:styled-content> at young age but without family history is 2\/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.605","type":"journal-article","created":{"date-parts":[[2019,2,27]],"date-time":"2019-02-27T08:16:52Z","timestamp":1551255412000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Exome sequencing in 51 early onset non\u2010familial <scp>CRC<\/scp> cases"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9306-844X","authenticated-orcid":false,"given":"Jessada","family":"Thutkawkorapin","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm 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