From VACTERL-H to heterotaxy: variable expressivity of ZIC3-related disorders

The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Ontario, Canada.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 05/2011; 155A(5):1123-8. DOI: 10.1002/ajmg.a.33859
Source: PubMed


The ZIC3 gene encodes a zinc finger protein which functions as a transcription factor in early stages of left-right body axis formation. Mutations in this X-linked gene cause a variety of clinical manifestations including heterotaxy, complex or isolated heart defect as well as other midline urogenital and hindgut malformations. We report a four generation family with X-linked heterotaxy associated with a deletion of the ZIC3 gene at Xq26.3. The index fetus of our proband showed classical features of heterotaxy while her maternal uncle and one brother had imperforate anus and her other brother had features suggestive of VACTERL-H without heterotaxy. A 1.4 Mb deletion in Xq26.3 including the ZIC3 gene was found in the fetus. Six females in the family were found to be asymptomatic carriers. Our report indicates that some of the cases with VACTERL-H syndrome may be caused by a mutation or deletion of the ZIC3 gene.

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    • "Recent reports additionally associate ZIC3 mutations with VAC- TERL, a constellation of defects (vertebral, anal, cardiac, tracheoesophageal , renal, radial, and limb) demonstrating phenotypic overlap with heterotaxy [Chung et al., 2011; Wessels et al., 2010]. A polyalanine tract expansion in one of these patients [Wessels et al., 2010] is particularly intriguing as similar tract expansions have been associated with a variety of human genetic disorders, including holoprosencephaly caused by mutations in ZIC2 [Messaed and Rouleau, 2009]. "
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    ABSTRACT: Mutations in zinc-finger in cerebellum 3 (ZIC3) result in heterotaxy or isolated congenital heart disease (CHD). The majority of reported mutations cluster in zinc-finger domains. We previously demonstrated that many of these lead to aberrant ZIC3 subcellular trafficking. A relative paucity of N- and C-terminal mutations has, however, prevented similar analyses in these regions. Notably, an N-terminal polyalanine expansion was recently identified in a patient with VACTERL, suggesting a potentially distinct function for this domain. Here, we report ZIC3 sequencing results from 440 unrelated patients with heterotaxy and CHD, the largest cohort yet examined. Variants were identified in 5.2% of sporadic male cases. This rate exceeds previous estimates of 1% and has important clinical implications for genetic testing and risk-based counseling. Eight of 11 were novel, including 5 N-terminal variants. Subsequent functional analyses included 4 additional reported but untested variants. Aberrant cytoplasmic localization and decreased luciferase transactivation were observed for all zinc-finger variants, but not for downstream or in-frame upstream variants, including both analyzed polyalanine expansions. Collectively, these results expand the ZIC3 mutational spectrum, support a higher than expected prevalence in sporadic cases, and suggest alternative functions for terminal mutations, highlighting a need for further study of these domains. This article is protected by copyright. All rights reserved.
    Full-text · Article · Feb 2014 · Human Mutation
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    • "Screening of HOXD13 and PCSK5 did not reveal any obvious pathogenic mutations and their role in the etiology of VACTERL remains unclear, however, it is possible that the detected PCSK5 variants could represent pathogenic variants with reduced penetrance. For further investigation of genes implicated in VACTERL association, it would be of interest to perform mutation screening of ZIC3, a gene associated with X-linked heterotaxy in which mutations have been detected in a few patients with VACTERL association phenotypes [13], [32]. "
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    ABSTRACT: In order to identify genetic causes of VACTERL association (V vertebral defects, A anorectal malformations, C cardiac defects, T tracheoesofageal fistula, E esophageal atresia, R renal anomalies, L limb deformities), we have collected DNA samples from 20 patients diagnosed with VACTERL or with a VACTERL-like phenotype as well as samples from 19 aborted fetal cases with VACTERL. To investigate the importance of gene dose alterations in the genetic etiology of VACTERL association we have performed a systematic analysis of this cohort using a 180K array comparative genomic hybridization (array-CGH) platform. In addition, to further clarify the significance of PCSK5, HOXD13 and CHD7 genes in the VACTERL phenotype, mutation screening has been performed. We identified pathogenic gene dose imbalances in two fetal cases; a hemizygous deletion of the FANCB gene and a (9;18)(p24;q12) unbalanced translocation. In addition, one pathogenic mutation in CHD7 was detected, while no apparent disease-causing mutations were found in HOXD13 or PCSK5. Our study shows that although large gene dose alterations do not seem to be a common cause in VACTERL association, array-CGH is still important in clinical diagnostics to identify disease cause in individual cases.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "In view of its X-linked transmission, it is termed X-linked VATER/VACTERL-hydrocephalus (or VACTERL-H), which can be caused by mutations in the ZIC3 gene. The same gene has been described to be responsible for the Xlinked visceral heterotaxy-1 [Wessels et al., 2010; Chung et al., 2011]. Wessels et al. [2010] reported a male infant with a ZIC3 polyalanine expansion associated with VATER/VACTERL phenotype without hydrocephalus. "
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    ABSTRACT: The VATER/VACTERL association is typically defined by the presence of at least 3 of the following congenital malformations: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. The involvement of genetic factors in the development of this rare association is suggested by reports of familial occurrence, the increased prevalence of component features among first-degree relatives of affected individuals, high concordance rates among monozygotic twins, chromosomal (micro-)aberrations or single gene mutations in individuals with the VATER/VACTERL phenotype, as well as murine knock-out models. Despite substantial efforts over the past decade, the genetic etiology of the VATER/VACTERL association in most instances remains elusive. The application of new genomic technologies such as high-resolution copy number variation studies or next-generation exome sequencing might lead to the identification of some of these causes.
    Full-text · Article · Feb 2013 · Molecular syndromology
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