Mutational analysis of <i>SHH</i> and <i>GLI3</i> in anorectal malformations

García-Barceló, María-Mercé; Lui, Vincent Chi-Hang; Miao, Xiaoping; So, Man-Ting; Leon, Thomas Y.Y.; Yuan, Zhenwei; Li, Long; Liu, Lei; Wang, Bin; Sun, Xiao-bing; Huang, Liuming; Tou, Jinfa; Ngan, Elly Sau-Wai; Cherny, Stacey S.; Chan, Kin Wai; Lee, Kim-Hung; Wang, Weiling; Wong, Kenneth K.; Tam, Paul Kwong‐Hang

doi:10.1002/bdra.20482

Cited by 18 publications

(11 citation statements)

References 17 publications

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“…Significantly lower SHH , GLI2 , and BMP4 expression was noted in the posterior wall of the terminal rectum in patients with ARM when compared with controls (Zhang et al, ). Mutation screening, however, did not reveal relevant functional mutations in SHH or GLI3 in two studies with 15 and 88 patients, respectively (Seri et al, ; Garcia‐Barcelo et al, ). Single‐nucleotide polymorphisms (SNPs) at predicted regulatory sites in (downstream) targets of the SHH pathway, including GLI family zinc finger 2 ( GLI2 ), homeobox D12 ( HOXD12 ), BMP4 , and proprotein convertase subtilisin/kexin type 5 ( PCSK5 ), were suggested to be associated with isolated ARM in a study with patients of several ethnic populations.…”

Section: Genetic Factorsmentioning

confidence: 98%

Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review

Wijers

Rooij

Marcelis

et al. 2014

Birth Defects Research Pt C

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Congenital anorectal malformations (ARMs) are one of the most frequently observed birth defects of the digestive system. However, their etiology remains elusive. Therefore, we aim to summarize and critically appraise all existing literature on the genetic and nongenetic etiology of nonsyndromic ARM and to conclude with unifying hypotheses and directions for future research. A structured literature search on English language human studies was conducted in PubMed and Embase up to October 1, 2013, resulting in 112 included articles. Research on the identification of genes underlying nonsyndromic ARM is remarkably scarce. Most studies were focused on screening of candidate genes for mutations or single-nucleotide polymorphisms, which did not yield any substantial evidence. Nongenetic factors fairly consistently found to be associated with ARM are assisted reproductive techniques, multiple pregnancy, preterm delivery, low birth weight, maternal overweight or obesity, and preexisting diabetes. This review provides indications for the involvement of both genes and nongenetic risk factors in the etiology of ARM. In future studies, large cohorts of patients with ARM from national and international collaborations are needed to acquire new hypotheses and knowledge through hypothesis-generating approaches. Challenges for future studies may also lie in the investigation of gene-gene and gene-environment interactions.

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Section: Genetic Factorsmentioning

confidence: 98%

Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review

Wijers

Rooij

Marcelis

et al. 2014

Birth Defects Research Pt C

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“…Teratogen-based animal models further support this hypothesis [40,41]. As humans with loss-of-function mutations affecting the SHH pathway have holoprosencephaly, it is unsurprising that patients with isolated VACTERL association do not have SHH mutations [42-44]. However, it is certainly possible that perturbations of SHH signaling due to interacting pathways may result in VACTERL association without brain anomalies.…”

Section: Aetiologymentioning

confidence: 99%

VACTERL/VATER Association

Solomon

2011

Orphanet Journal of Rare Diseases

365

356

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VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment.

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“…Although argument has been made for disturbance of the SHH pathway as a cause for VACTERL association, no specific mutations in SHH or the closely related GLI genes have been found in patients with VACTERL association [Garcia-Barceló et al, 2008a;Aguinaga et al, 2010]. Mutations in Shh, Gli2 , and Gli3 have produced VACTERL malformations in mice [Kim et al, 2001].…”

Section: Molecular Pathways Involved In Formation Of Anatomical Strucmentioning

confidence: 99%

Considering the Embryopathogenesis of VACTERL Association

Stevenson

Hunter²

2013

Mol Syndromol

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The nonrandom co-occurrence of vertebral, anorectal, cardiac, tracheoesophageal, genitourinary, and limb malformations, recognized as the VACTERL association, has not been satisfactorily explained from either a causation or embryopathogenesis standpoint. Few familial cases have been identified and maternal diabetes is the only environmental influence implicated to date. Mutations in single genes have been found in a number of syndromes with one or more of the VACTERL malformations, but these syndromes usually have other features which distinguish them from the VACTERL association. Animal models have provided clues to molecular pathways that may be involved in the embryogenesis of the VACTERL structures. What is lacking is the systematic study of individual genes and pathways in well-composed cohorts of patients, which is now possible with high throughput molecular technologies.

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Mutational analysis of SHH and GLI3 in anorectal malformations

Abstract: These variants are not over-represented in the healthy population and most are predicted to be benign. This study conveys the problematic assessment of the pathogenic role in disease of rare point mutations and variants.

Cited by 18 publications

References 17 publications

Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review

Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review

VACTERL/VATER Association

Considering the Embryopathogenesis of VACTERL Association

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