Cytogenetically Balanced Reciprocal Translocation Could Hide Molecular Genomic Unbalances: Implications for Foetal Phenotype Correlation

Abstract

When an increased nuchal translucency (>3.00 mm) is observed during the echographic examination of a foetus in the first trimester of pregnancy, an increased risk of chromosomopathy is considered, and the pregnant woman is offered the possibility of an invasive investigation. Here, we focused our attention on prenatal diagnosis issues in cases of foetuses with cytogenetically balanced reciprocal translocations. We report the finding of a cytogenetically balanced, de facto genomically unbalanced translocation that poses a challenge in a case of prenatal diagnosis, changing the risk of Down syndrome in a Zellweger syndromic spectrum risk (PEX3 deletion). At term, a healthy baby was born. This case teaches that prenatal diagnosis in cases of foetuses at increased risk of chromosomal abnormality imperatively requires molecular investigation in addition to a morphological karyotype.

Keywords: PEX3 gene; chromosomal translocation; cytogenetic analysis; genomic comparative hybridisation array; genomic deletion; prenatal diagnosis.

Figure 1

A 42-year-old G3P0 pregnant woman (2 first trimester miscarriages) was seeking prenatal diagnosis due to advanced age. On the first ultrasound, there was an increased nuchal translucency, 3.2 mm, while the general development was in the normal range. The combined test (PAPP-A and free beta-HCG) resulted in a high risk for trisomy 21, 1:5, and trisomy 13, 1:62. A chorionic villus sampling was performed at 12.5 weeks gestational age from cytotrophoblasts and after cultures of mesenchymal tissue; a male karyotype was observed with an apparently balanced translocation involving chromosomes 3 and 6 (A). The extension of the chromosomal analysis to parents showed the same translocation in the paternal karyotype and allowed us to define the breakpoints in 3q25.1 and 6q24.2 (B). The maternal karyotype was normal. At the same time, a CGH array was performed during a placental biopsy and deletion was evident: arr[GRCh37] 6q24.2(143512294_144136217,)x1 (C,D). The deletion was heterozygous, at a size of 624 Kb of chromosome 6 at cytoband q24.2, and it included the OMIM gene PEX3.

Figure 2

In our case, it could be hypothesised that the mechanism that produced the translocation also produced the micro-deletion in the genome; in fact, the break point of the micro-deletion maps in the cytogenetic band 6q24, according to the CGH array results.