X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3

Abstract

We report on a Lebanese family in which two maternal cousins suffered and died very early in life from cardiac malformations. Both presented with a transposition of the great arteries associated with one or several other cardiac defects. Various minor midline defects were also observed, but there were no situs abnormalities other than a persistent left superior vena cava in one. A maternal uncle of these two babies was born cyanotic and died on the third post-natal day. Analysis of the ZIC3 gene, revealed the presence of a mutation in the second exon leading to a truncation of the protein. Surprisingly, another maternal uncle of the two affected cousins also had the mutation but was not clinically affected. To our knowledge, this is the first instance of incomplete penetrance in a male for a mutation in a chromosome X gene.

Missense Mutations and Gene Interruption in PROSIT240 , a Novel TRAP240 -Like Gene, in Patients With Congenital Heart Defect (Transposition of the Great Arteries)

“…Surprisingly, a healthy, maternal uncle also showed the same mutation, pointing toward incomplete penetrance. 8 Besides ZIC3, the EGF-CFC gene CFC1 represents an interesting candidate because of gene-targeting studies in mice. CFC1 Ϫ/Ϫ mice develop laterality defects and complex cardiac malformations reminiscent of human heterotaxy syndrome.…”

“…Understanding more about the mechanisms leading to dTGA might also help to determine whether dTGA could be considered a manifestation of a left-right laterality defect concerning the heart, a point that has been raised based on data from animal models 35,36 and the fact that ZIC3 and CFC1 mutations are detected both in patients with dTGA and in heterotaxy problems. 8,11 In animal models, most interestingly, Pitx2 Ϫ/Ϫ and Dvl Ϫ/Ϫ mice present with outflow tract abnormalities, including TGA and laterality defects. Both genes are part of the Wnt/Dvl/␤-catenin 3 Pitx2 pathway, which was shown to recruit TRAP components.…”

“…6,7 However, because historically only a few TGA patients survived to reproductive age, very little is known about the recurrence risk in offspring. Until now, mutations in 2 genes were thought to be associated with the pathogenesis of TGA in humans: ZIC3 8 and CFC1 (human CRYPTIC gene). 9 Both genes were originally characterized in patients with heterotaxic phenotypes (randomized organ positioning) 10,11 and subsequently screened for mutations in patients with TGA.…”

Ocular pathology in congenital heart disease

“…1,2 Both environmental factors and genetic factors have been implicated. 1,2 Ocular studies in CHD are few and have concentrated on one cardiac anomaly, [3][4][5][6][7][8] one syndrome with cardiac anomaly, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] small series, single case reports, [26][27][28] or literature review. 29 Ocular findings in CHD were not revisited for the past 25 years.…”

Molecular Genetic Analysis of CRELD1 in Patients with Heterotaxy Disorder

“…In addition, affected females have been described with point mutations or with chromosomal translocations at this gene (Megarbane et al, 2000;Fritz et al, 2005;Tzschach et al, 2006;Chhin et al,2007).…”