Situs ambiguus in a female fetus with balanced (X;21) translocation--evidence for functional nullisomy of the ZIC3 gene?
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 beta-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.
Fritz
Barbara
B
Institut für Klinische Genetik der Philipps-Universität Marburg, Germany. fritzb@staff.uni-marburg.de
Kunz
Jürgen
J
Knudsen
Gun Peggy Strømstad
GP
Louwen
Frank
F
Kennerknecht
Ingo
I
Eiben
Bernd
B
Orstavik
Karen Helene
KH
Friedrich
Ursula
U
Rehder
Helga
H
D002891:Chromosomes, Human, Pair 21; D041321:Chromosomes, Human, X; D004303:Dosage Compensation, Genetic; D005260:Female; D005318:Fetal Heart / Q000002:abnormalities* / Q000000981:diagnostic imaging; D018392:Genomic Imprinting; D018398:Homeodomain Proteins; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011859:Radiography; D011944:Receptors, Androgen / Q000235:genetics; D012729:Sex Chromosome Aberrations; D012857:Situs Inversus / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics
D018398:Homeodomain Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; C491595:ZIC3 protein, human