De novo GLI3 mutation in esophageal atresia: Reproducing the phenotypic spectrum of Gli3 defects in murine models

Yang, Lin; Shen, Chun; Mei, Mei; Zhan, Guodong; Zhao, Yunke; Wang, Huijun; Huang, Guoying; Qiu, Zilong; Lu, Weineng; Zhou, Wenhao

doi:10.1016/j.bbadis.2014.05.001

Cited by 9 publications

(4 citation statements)

References 31 publications

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“…However, neither a literature review nor the reviews of 174 GCPS/PHS patients, provided by Johnston et al (19,20), revealed the presence of our GLI3 splice variant or EA/TEF in these patients. Yet, Yang et al (21) reported a de novo missense GLI3 variant (p.M111T) in a patient with EA with hemivertebrae, resembling the phenotypic spectrum in murine models as reported by Motoyama et al (10).…”

Section: Discussionmentioning

confidence: 64%

Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchio‑otic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?

et al. 2017

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Branchio‑otic (BO) syndrome is a clinically and genetically heterogeneous disorder that presents with variable branchial arch and otic anomalies. Dominant mutations in the human homologues of the Drosophila eyes absent (EYA1) gene, and the Drosophila sine oculis homeobox 1 and 5 (SIX1 and SIX5, respectively) genes have been causally associated with BO syndrome. Esophageal atresia (EA), with or without tracheo‑esophageal fistula (TEF), is the most common type of malformation of the upper digestive tract. To date, its causes are poorly understood. The present study investigated a family with three affected members who all presented with classic BO associated symptoms. Notably, the index patient also presented with the most common EA/TEF subtype type 3b. Whole exome sequencing (WES) was performed in the index patient, and prioritized genetic variants and their segregation in the family were analyzed by Sanger sequencing. WES demonstrated a known disease‑causing heterozygous EYA1 splice variant in the patient, as well as his sister and mother; all of whom were affected with BO syndrome. A further GLI family zinc finger 3 (GLI3) splice variant of unknown significance, inherited from the unaffected father, was also detected in the index patient. EYA1 and GLI3 are involved in the Sonic Hedgehog transcriptional network and GLI3 seems to be involved in human foregut malformations. Therefore, one may hypothesize a digenic inheritance model involving EYA1 and GLI3, where the effect of the GLI3 variant observed here only emerges in the background of the EYA1 defect.

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Section: Discussionmentioning

confidence: 64%

Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchio‑otic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?

et al. 2017

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“…More data would be necessary to determine if EA/TEF could be a minor feature of these syndromes. A GLI3 mutation has already been reported in a patient with EA [Yang L et al, 2014]. However, the variant found in the patient from this cohort appeared to be a non-deleterious polymorphism present in 0.6% of the European population (ExAC; http://exac.broadinstitute.org), even though it was previously thought to be associated with Greig cephalopolydactyly [Kalff-Suske et al, 1999;Krauss et al, 2009].…”

Section: Diagnoses In This Cohortmentioning

confidence: 59%

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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“…Likewise, the incidence of chromosome anomalies is increased in EA, with an incidence of 6 to 10 % for whole chromosome aneuploidy and an additional 1 to 2 % for copy number variants [17]. Single gene deletions, such as SHH and GLI3 , have previously been implicated in animal models of EA, and more recently reported in human cases [18–20]. Therefore, it is appropriate to offer prenatal diagnosis, which aids in the management of pregnancy and informs postnatal care of the neonate.…”

Section: Discussionmentioning

confidence: 99%

Twin pregnancy complicated by esophageal atresia, duodenal atresia, gastric perforation, and hypoplastic left heart structures in one twin: a case report and review of the literature

Chaar¹,

Meyers

Tucker

et al. 2017

J Med Case Reports

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BackgroundThe antenatal diagnosis of a combined esophageal atresia without tracheoesophageal fistula and duodenal atresia with or without gastric perforation is a rare occurrence. These diagnoses are difficult and can be suspected on ultrasound by nonspecific findings including a small stomach and polyhydramnios. Fetal magnetic resonance imaging adds significant anatomical detail and can aid in the diagnosis of these complicated cases. Upon an extensive literature review, there are no reports documenting these combined findings in a twin pregnancy. Therefore we believe this is the first case report of an antenatal diagnosis of combined pure esophageal and duodenal atresia in a twin gestation.Case presentationWe present a case of a 30-year-old G1P0 white woman at 22-week gestation with a monochorionic-diamniotic twin pregnancy discordant for esophageal atresia, duodenal atresia with gastric perforation, hypoplastic left heart structures, and significant early gestation maternal polyhydramnios. In this case, fetal magnetic resonance imaging was able to depict additional findings including area of gastric wall rupture, hiatal hernia, dilation of the distal esophagus, and area of duodenal obstruction and thus facilitated the proper diagnosis. After extensive counseling at our multidisciplinary team meeting, the parents elected to proceed with radiofrequency ablation of the anomalous twin to maximize the survival of the normal co-twin. The procedure was performed successfully with complete cessation of flow in the umbilical artery and complete cardiac standstill in the anomalous twin with no detrimental effects on the healthy co-twin.ConclusionsPrenatal diagnosis of complex anomalies in twin pregnancies constitutes a multitude of ethical, religious, and cultural factors that come into play in the management of these cases. Fetal magnetic resonance imaging provides detailed valuable information that can assist in management options including possible prenatal intervention. The combination of a cystic structure with peristalsis-like movement above the diaphragm (for example, “the upper thoracic pouch sign”), polyhydramnios, and progressive distention of the stomach and duodenum should increase suspicion for a combined pure esophageal and duodenal atresia.

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De novo GLI3 mutation in esophageal atresia: Reproducing the phenotypic spectrum of Gli3 defects in murine models

Cited by 9 publications

References 31 publications

Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchio‑otic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?

Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchio‑otic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?

Genetic Testing in a Cohort of Complex Esophageal Atresia

Twin pregnancy complicated by esophageal atresia, duodenal atresia, gastric perforation, and hypoplastic left heart structures in one twin: a case report and review of the literature

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