Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate<i>ZIC3</i>and<i>FOXF1</i>in Human VATER/VACTERL Association

Hilger, Alina C.; Halbritter, Jan; Pennimpede, Tracie; Ven, Amelie van der; Sarma, Georgia; Braun, Daniela A.; Porath, Jonathan D.; Kohl, Stefan; Hwang, Daw-Yang; Dworschak, Gabriel C.; Hermann, Bernhard G.; Pavlova, Anna; El‐Maarri, Osman; Nöthen, Markus M.; Ludwig, Michael; Reutter, Heiko; Hildebrandt, Friedhelm

doi:10.1002/humu.22859

Cited by 48 publications

(47 citation statements)

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“…The deletion of genes in the Sonic hedgehog pathway (for example SHH , GLI , and HOXD13 ) modeled in mice mimics many of the same malformations as found in VACTERL association, which have resulted in a profound interest in these genes [40]. However, only mutations of HOXD13 [41] and FOXF1 [42, 43] have been reported in humans with VACTERL association, while SHH and GLI2 mutations are associated with holoprosencephaly [40]. Furthermore, mutations in ZIC3 have been reported in several cases of VACTERL association [43–45].…”

Section: Discussionmentioning

confidence: 99%

“…However, only mutations of HOXD13 [41] and FOXF1 [42, 43] have been reported in humans with VACTERL association, while SHH and GLI2 mutations are associated with holoprosencephaly [40]. Furthermore, mutations in ZIC3 have been reported in several cases of VACTERL association [43–45]. Several copy number variations (CNVs) have been reported (thoroughly reviewed by Brosens et al [46]), of which recurrent de novo CNVs have been reported at 8q24.3 ( GLI4 ) and 17q23 ( TBX2 / TBX4 ).…”

Section: Discussionmentioning

confidence: 99%

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Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

et al. 2016

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BackgroundThe vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome are rare conditions. We aimed to present two cases with the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser co-occurrence from our local surgical center and through a systematic literature search detect published cases. Furthermore, we aimed to collect existing knowledge in the embryopathogenesis and genetics in order to discuss a possible link between the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome.Case presentationOur first case was a white girl delivered by caesarean section at 37 weeks of gestation; our second case was a white girl born at a gestational age of 40 weeks. A co-occurrence of vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome was diagnosed in both cases.We performed a systematic literature search in PubMed ((VACTERL) OR (VATER)) AND ((MRKH) OR (Mayer-Rokitansky-Küster-Hauser) OR (mullerian agenesis) OR (mullerian aplasia) OR (MURCS)) without limitations. A similar search was performed in Embase and the Cochrane library. We added two cases from our local center.All cases (n = 9) presented with anal atresia and renal defect. Vertebral defects were present in eight patients. Rectovestibular fistula was confirmed in seven patients. Along with the uterovaginal agenesis, fallopian tube aplasia appeared in five of nine cases and in two cases ovarian involvement also existed.ConclusionsThe co-occurrence of the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome is extremely rare. This group of patients has unusual phenotypic characteristics. The long-term outcome after treatment of defects is not well reported. A single unifying cause is not known and the etiology probably includes both genetic and non-genetic causes. We stress the importance of future studies to optimized treatment, follow-up, and etiology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

et al. 2016

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“…For example, the importance of FoxF1 in gut morphogenesis was first demonstrated in Xenopus , as discussed above (section 3.4;[111]). Mutations in this gene have recently been detected in human patients with similar malformations, including intestinal malrotation and congenital short bowel [152–154]. Moreover, trisomy of chromosome 16, which contains the human foxf1 gene, is also associated with intestinal maladies [153] .…”

Section: From Frogs To Humansmentioning

confidence: 99%

“…Moreover, trisomy of chromosome 16, which contains the human foxf1 gene, is also associated with intestinal maladies [153] . Finally, mutations in zic3 , a transcription factor involved in directing organ laterality in animal models [155], have recently been detected in humans with congenital GI defects [152]. In Xenopus , overexpression of zic3 , or injection of a mutant zic3 mRNA that acts in a dominant-negative manner, disrupt the direction of intestinal looping, providing in vivo confirmation of the suspected role of this molecule in organogenesis [155].…”

Section: From Frogs To Humansmentioning

confidence: 99%

Frogs as integrative models for understanding digestive organ development and evolution

Womble

Pickett

Nascone-Yoder

2016

Seminars in Cell & Developmental Biology

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The digestive system comprises numerous cells, tissues and organs that are essential for the proper assimilation of nutrients and energy. Many aspects of digestive organ function are highly conserved among vertebrates, yet the final anatomical configuration of the gut varies widely between species, especially those with different diets. Improved understanding of the complex molecular and cellular events that orchestrate digestive organ development is pertinent to many areas of biology and medicine, including the regeneration or replacement of diseased organs, the etiology of digestive organ birth defects, and the evolution of specialized features of digestive anatomy. In this review, we highlight specific examples of how investigations using Xenopus laevis frog embryos have revealed insight into the molecular and cellular dynamics of digestive organ patterning and morphogenesis that would have been difficult to obtain in other animal models. Additionally, we discuss recent studies of gut development in non-model frog species with unique feeding strategies, such as Lepidobatrachus laev is and Eleutherodactylouscoqui, which are beginning to provide glimpses of the evolutionary mechanisms that may generate morphological variation in the digestive tract. The unparalleled experimental versatility of frog embryos make them excellent, integrative models for studying digestive organ development across multiple disciplines.

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“…Otherwise, it has been shown that some signaling pathways, such as sonic hedgehog, Hox and retinoic acid pathways could also be implicated in the etiology [Solomon, 2011;Brosens et al, 2014]. Individuals with VAC-TERL features were identified with mutations of ZIC3 and FOXF1 [Chung et al, 2011;Hilger et al, 2015], FGF8 [Zeidler et al, 2014], PTEN [Reutter and Ludwig, 2013], and HOXD13 [Garcia-Barcelo et al, 2008]. A study of 69 twins affected by VACTERL association did not show a higher concordance rate in monozygotic twins than in dizygotic twins, and therefore suggested that inherited genetic factors play a limited role in this condition [Bartels et al, 2012b].…”

Section: Vacterl Associationmentioning

confidence: 99%

Genetic Testing in a Cohort of Complex Esophageal Atresia

et al. 2017

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The objective of the present study is to describe a cohort of complex esophageal atresia and the yield of genetic tests performed for such patients. We selected 45 patients with complex esophageal atresia (EA), namely those having at least one associated anomaly. We reviewed their medical records to assess clinical features, other diagnoses, and genetic investigations. Most of the patients had a diagnosis of VACTERL association (56%) with no genetic variant identified. Interestingly, 5 patients in the cohort (11%) had a right pulmonary hypoplasia or agenesis. A majority of our cohort (73%) had genetic testing; 60% were karyotyped (abnormal in 4 of the 27 patients tested), 31% had aCGH (abnormal in 1 of the 14 patients tested), and 31% had diepoxybutane (DEB) testing for Fanconi anemia (abnormal in 2 of the 14 patients tested). One patient had exome sequencing studies, but no candidate gene was identified. Various anomalies were associated with EA, and overall a genetic variant could be identified in 7 of the 33 patients tested. Chromosomal studies such as aCGH and chromosomal breakage studies should be considered, and their yield varied between 7 and 14%. Other genetic investigations such as exome sequencing could possibly have even higher yields but will need to be assessed in a large cohort. Improved genetic diagnoses in EA may improve the management of these patients by directing specific surveillance and management schemes.

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Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies ImplicateZIC3andFOXF1in Human VATER/VACTERL Association

Cited by 48 publications

References 25 publications

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

Frogs as integrative models for understanding digestive organ development and evolution

Genetic Testing in a Cohort of Complex Esophageal Atresia

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