Situs ambiguus in a female fetus with balanced (X;21) translocation – evidence for functional nullisomy of the ZIC3 gene?

Abstract

The human ZIC3 gene has been mapped to Xq26.2, the visceral heterotaxy locus HTX1, and has been shown to be mutated in X-linked situs ambiguus and/or complex heart defects. We report on a female fetus with situs ambiguus, asplenia and corrected transposition of the great arteries, displaying a (X;21) translocation. The balanced state of the t(X;21)(q26;p13) was verified by FISH on metaphase chromosomes of the fetus using DOP-PCR products of the microdissected der(21) and Xq-subtelomere specific sequences, and by PRINS with b-satellite specific sequences. Examination with polymorphic markers flanking ZIC3 on DOP-PCR products of the microdissected der(21) chromosome evidenced that the complete copy of the ZIC3 gene was translocated to chromosome 21. Mutations in the fetal and parental ZIC3 genes were excluded by sequencing. Paternal origin of the der(X) and der(21) chromosomes was confirmed by use of polymorphic microsatellite markers from chromosome 21 and from the chromosomal region Xq26, respectively. X chromosome inactivation analysis using a PCR of a polymorphic (CAG) n repeat in the first exon of the androgen receptor gene showed a completely skewed X inactivation pattern with the paternal X as the active X chromosome, thus excluding functional disomy of distal Xq. A positional effect caused by the balanced (X;21) translocation may be responsible for functional nullisomy of ZIC3 and thus explain the situs and cardiac abnormalities in the fetus.

Heterotaxy and cardiac defect in a girl with chromosome translocation t(X;1)(q26;p13.1) and involvement of ZIC3

“…7 In contrast to our patient, the previously reported foetus with an X;21 translocation had asplenia, bilaterally four-lobed lungs and sacral hypoplasia as additional features. The parents of this foetus decided to terminate the pregnancy.…”

“…10,11 This was also the case in the foetus reported by Fritz et al 7 Skewed X-inactivation was also present in our patient, thus mimicking the situation in hemizygous males (functional nullisomy). The specific phenotype of our patient is very likely caused by the absence of functional ZIC3, probably owing to disruption of the transcriptional unit from a regulatory element or owing to a position effect associated with the translocation breakpoints.…”

“…This situation has recently been reported in a female foetus with a balanced translocation t(X;21)(q26;p13) and the clinical features of ZIC3 mutations (situs ambiguus and cardiac malformations). 7 Here, we report on a 2-year-old girl with a chromosome breakpoint in the ZIC3 region and congenital complex heart malformation, situs ambiguus and normal psychomotor development.…”

From VACTERL‐H to heterotaxy: Variable expressivity of ZIC3—related disorders

“…This is opposite to the cases where the disruption of the ZIC3 gene was the result of X-autosome translocation. In these cases there will be functional nullisomy and the female carriers have severe phenotype [Fritz et al, 2005;Tzschach et al, 2006].…”

Genetics of human heterotaxias

“…For example, a few heterotaxy patients carrying balanced reciprocal translocations or inversion have been observed, 8,9 including a recent report of a balanced (X;21) translocation involving a nonmutated but potentially inactivated ZIC3 gene region. 10 This review will summarize current clinical and basic research approaches to these interesting disorders.…”