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Additionally, humans with decreased NAD+ production due to changes in pathway genes display similar malformations. Here, I hypothesize NAD+ deficiency as a pleiotropic mechanism for multiple malformation conditions, including limb\u2010body wall complex (LBWC), pentalogy of Cantrell (POC), omphalocele\u2010exstrophy\u2010imperforate anus\u2010spinal defects (OEIS) complex, vertebral\u2010anal\u2010cardiac\u2010tracheoesophageal fistula\u2010renal\u2010limb (VACTERL) association (hereafter VACTERL), oculoauriculovertebral spectrum (OAVS), Mullerian duct aplasia\u2010renal anomalies\u2010cervicothoracic somite dysplasia (MURCS), sirenomelia, and urorectal septum malformation (URSM) sequence, along with miscarriages and other forms of congenital malformation. The term Congenital NAD Deficiency Disorder (CNDD) could be considered for patients with these malformations; however, it is important to emphasize there have been no confirmatory experimental studies in humans to prove this hypothesis. In addition, these multiple malformation conditions should not be considered individual entities for the following reasons: First, there is no uniform consensus of clinical diagnostic criteria and all of them fail to capture cases with partial expression of the phenotype. Second, reports of individuals consistently show overlapping features with other reported conditions in this group. Finally, what is currently defined as VACTERL is what I would refer to as a default label when more striking features such as body wall defects, caudal dysgenesis, or cloacal exstrophy are not present.<\/jats:p>","DOI":"10.1002\/ajmg.a.62764","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T07:40:37Z","timestamp":1651218037000},"page":"2834-2849","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["<scp>NAD<\/scp>+ deficiency in human congenital malformations and miscarriage: A new model of pleiotropy"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-888X","authenticated-orcid":false,"given":"Paul R.","family":"Mark","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Medical Genetics Helen DeVos Children's Hospital, Spectrum Health  Grand Rapids Michigan USA"},{"name":"Department of Pediatrics and Human Development College of Human Medicine, Michigan State University  Grand Rapids Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-0705.2000.00233.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61847"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-020-03609-4"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdr2.1512"},{"issue":"3","key":"e_1_2_8_6_1","first-page":"85","article-title":"Two rare cases of the pentalogy of Cantrell or its variants","volume":"31","author":"Aslan A.","year":"2004","journal-title":"Acta Medica Austriaca"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/07315724.2002.10719191"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000360080"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-012-3100-z"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.058"},{"key":"e_1_2_8_11_1","volume-title":"Human malformations and related anomalies","author":"Blackburn W.","year":"2006"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdr2.1049"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.05.023"},{"key":"e_1_2_8_14_1","first-page":"602","article-title":"A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart","volume":"107","author":"Cantrell J. 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