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OFDS is inherited both in an X\u2010linked dominant, X\u2010linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in<jats:italic>CEP164<\/jats:italic>, a gene associated with ciliopathy\u2010spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical<jats:italic>TOPORS<\/jats:italic>missense variant, c.29 C&gt;A; (p.Pro10Gln). Heterozygous<jats:italic>TOPORS<\/jats:italic>pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.<\/jats:p>","DOI":"10.1002\/ajmg.a.62337","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T05:40:40Z","timestamp":1623822040000},"page":"2409-2416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Expanding the genetic landscape of oral\u2010facial\u2010digital syndrome with two novel genes"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9261-244X","authenticated-orcid":false,"given":"Alanna","family":"Strong","sequence":"first","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"},{"name":"The Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Simone","sequence":"additional","affiliation":[{"name":"Center for Genetic and Genomic Medicine Hackensack University Medical Center Hackensack New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Krentz","sequence":"additional","affiliation":[{"name":"PreventionGenetics Marshfield Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Vaccaro","sequence":"additional","affiliation":[{"name":"The Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Watson","sequence":"additional","affiliation":[{"name":"The Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley","family":"Ron","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1500-9713","authenticated-orcid":false,"given":"Jennifer M.","family":"Kalish","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helio F.","family":"Pedro","sequence":"additional","affiliation":[{"name":"Center for Genetic and Genomic Medicine Hackensack University Medical Center Hackensack New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine H.","family":"Zackai","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2814-7461","authenticated-orcid":false,"given":"Hakon","family":"Hakonarson","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"},{"name":"The Center for Applied Genomics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics, Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Division of Pulmonary Medicine Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-019-04267-x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61018"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014101051"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2009.05.025"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.4103\/jnrp.jnrp_338_17"},{"key":"e_1_2_9_7_1","first-page":"922","article-title":"Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa","volume":"14","author":"Bowne S. 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