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Sanger sequencing was used to confirm sequence variations and their segregation with the disease phenotype. The co\u2010occurrence of <jats:italic>ENAM<\/jats:italic> and <jats:italic>LAMA3<\/jats:italic> mutations in one family raised the possibility of digenic inheritance. Enamel formed in <jats:italic>Enam<jats:sup>+\/+<\/jats:sup>Ambn<\/jats:italic><jats:sup>+\/+<\/jats:sup>, <jats:italic>Enam<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic>, <jats:italic>Ambn<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic>, and <jats:italic>Enam<jats:sup>+\/\u2212<\/jats:sup>Ambn<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> mice was characterized by dissection and backscattered scanning electron microscopy (bSEM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>ENAM<\/jats:italic> mutations segregating with AI in five families were identified. Two novel <jats:italic>ENAM<\/jats:italic> frameshift mutations were identified. A single\u2010nucleotide duplication (c.395dupA\/p.Pro133Alafs*13) replaced amino acids 133\u20101142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single\u2010nucleotide deletion (c.2763delT\/p.Asp921Glufs*32) replaced amino acids 921\u20101142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single\u2010nucleotide <jats:italic>ENAM<\/jats:italic> deletion (c.588+1delG\/p.Asn197Ilefs*81). One of these families also harbored a heterozygous <jats:italic>LAMA3<\/jats:italic> mutation (c.1559G&gt;A\/p.Cys520Tyr) that cosegregated with both the AI phenotype and the <jats:italic>ENAM<\/jats:italic> mutation. In mice, <jats:italic>Ambn<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> maxillary incisors were normal. <jats:italic>Ambn<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> molars were also normal, except for minor surface roughness. <jats:italic>Ambn<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> mandibular incisors were sometimes chalky and showed minor chipping. <jats:italic>Enam<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> incisor enamel was thinner than normal with ectopic mineral deposited laterally. <jats:italic>Enam<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> molars were sometimes chalky and rough surfaced. <jats:italic>Enam<jats:sup>+\/\u2212<\/jats:sup>Ambn<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> enamel was thin and rough, in part due to ectopic mineralization, but also underwent accelerated attrition.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Novel <jats:italic>ENAM<\/jats:italic> mutations causing AI were identified, raising to 22 the number of <jats:italic>ENAM<\/jats:italic> variations known to cause AI. The severity of the enamel phenotype in <jats:italic>Enam<jats:sup>+\/\u2212<\/jats:sup>Ambn<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> double heterozygous mice is caused by composite digenic effects. Digenic inheritance should be explored as a cause of AI in humans.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.928","type":"journal-article","created":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T02:56:46Z","timestamp":1567479406000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["<i>ENAM<\/i> mutations and digenic inheritance"],"prefix":"10.1002","volume":"7","author":[{"given":"Hong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Figen","family":"Seymen","sequence":"additional","affiliation":[{"name":"Department of Pedodontics, Faculty of Dentistry Istanbul University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mine","family":"Koruyucu","sequence":"additional","affiliation":[{"name":"Department of Pedodontics, Faculty of Dentistry Istanbul University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yelda","family":"Kasimoglu","sequence":"additional","affiliation":[{"name":"Department of Pedodontics, Faculty of Dentistry Istanbul University Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih\u2010Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry Ann Arbor MI USA"},{"name":"Department of Dentistry National Taiwan University School of Dentistry Taipei City Taiwan R.O.C."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Timothy","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Pediatric Dentistry University of North Carolina School of Dentistry Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Havel","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung\u2010Wook","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry Seoul National University Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7192-6105","authenticated-orcid":false,"given":"James P.","family":"Simmer","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan C.\u2010C.","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biologic and Materials Sciences University of Michigan School of Dentistry Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,9,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00239-009-9302-x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/154405910408301204"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(96)00525-2"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/003591576706000965"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3526"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209100200"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034510365662"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034514522060"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.06120"},{"key":"e_1_2_7_13_1","first-page":"324","article-title":"Proximal renal tubular acidosis and ocular pathology: A novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1)","volume":"12","author":"Demirci F. 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