Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?

Wessels, Marja W.; Kuchinka, Brian D.; Heydanus, R.; Smit, Bert; Dooijes, Dennis; Krijger, Ronald R. de; Lequin, Maarten H.; Jong, Elisabeth M. de; Husen, Margreet; Willems, Patrick J.; Casey, Brett

doi:10.1136/jmg.2008.060913

Cited by 70 publications

(62 citation statements)

References 33 publications

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“…In particular, the ZIC3 p.(Ala55dup) variant was reported earlier in a series of heterotaxy cases 9,10 and a variant with an expansion of two alanine residues was reported in a case of VACTERL association. 11 However, the presence of an expansion of one alanine in 5% the American population casts serious doubt on its causality in any defect. We considered the classical large duplication in 22q11 as causal for the CHD in families MC074 and MC089 although with incomplete penetrance.…”

Section: Discussionmentioning

confidence: 99%

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

Malti¹,

Liu²,

Doray³

et al. 2015

Eur J Hum Genet

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The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 × ), NKX2-5 (6 × ), ZIC3 (3 × ), MLPA (2 × ) and ELN (4 × ). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.

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Section: Discussionmentioning

confidence: 99%

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

Malti¹,

Liu²,

Doray³

et al. 2015

Eur J Hum Genet

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“…One exception is the report of a missense mutation in ZIC3 , an X-linked gene associated with heterotaxy, in a patient who had all of the VACTERL malformations and whose cousin and a nephew had cardiovascular anomalies [Ware et al, 2004]. ZIC3 deletion or mutation has been reported in 2 other males who met criteria for VACTERL association [Wessels et al, 2010;Chung et al, 2011].…”

Section: Single Gene Mutations Among Conditions With Component Malformentioning

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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“…All have previously been described to be associated with ciliary dyskinesia in either mice or humans, and in some cases both. 16,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] We find it of significance, therefore, that a large proportion of affected genes are associated with not only isomerism, but also with ciliary dyskinesia. Previous studies have shown that over 40% of patients with isomerism also have ciliary dyskinesia.…”

Section: Discussionmentioning

confidence: 78%

Genetic Disturbances in Patients with Bodily Isomerism from a Single Center: Clinical Implications of Affected Genes and Potential Impact of Ciliary Dyskinesia

Loomba

Frommelt

Anderson³

2016

Cardiogenetics

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So-called heterotaxy or isomerism is characterized by abnormal lateralization and malformations of the bodily organs. The mechanism is unclear, although there is growing evidence that ciliary dyskinesia is involved. We reviewed genetic findings from patients with isomerism to determine if affected genes were known to be associated with isomerism and ciliary dyskinesia and determine associations between genotype and clinical findings. We identified patients with isomerism cared for over a 16-year period. Characteristics were compared between those with and without identified mutations. A total of 83 patients with isomerism were identified. Of those who had genotyping, 14/27 had mutations identified, most frequently involving the CFC1 and NODAL genes. Specific mutations were associated with clinical findings, with NODAL mutations often portending need for increased clinical support. Genes associated with isomerism and/or ciliary dyskinesia were identified in the cohort. Specific gene mutations may help predict clinical course.

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Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder?

Cited by 70 publications

References 33 publications

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

Considering the Embryopathogenesis of VACTERL Association

Genetic Disturbances in Patients with Bodily Isomerism from a Single Center: Clinical Implications of Affected Genes and Potential Impact of Ciliary Dyskinesia

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