41. Clinical significance of comprehensive genetic workup prior to use of assisted reproductive technology: A case study

      A 16-month-old female was seen at the genetics clinic due to hypotonia and significant developmental delay. The proband was the product of a twin pregnancy. Chromosome analysis as well as fragile X, Prader Willi and Angelman tests were all normal. Whole-genome microarray analysis revealed a 4.6 Mb interstitial copy number gain involving the distal part of the long arm of chromosome 3q28-q29 (chr3:190800735_195464853). Confirmatory metaphase FISH as well as whole-chromosome paint FISH revealed that the duplicated 3q28-q29 material is not tandem but rather inserted into the proximal long arm of chromosome 9, resulting in 46,XX,ins(9;3)(q21.2;q28q29). In order to determine the origin of this abnormality, FISH was performed on parental specimens. To our surprise, the maternal interphase FISH analysis revealed the loss of the 3q region. However, review of the metaphase FISH and subsequently maternal karyotype indicated that the deleted 3q region was in fact involved in an apparently unbalanced translocation between chromosomes 1 and 3 resulting in 46,XX,der(1)t(1;3)(q25.2;q28),der(3)?del(3)(q29)t(1;3). It is unclear how a maternal unbalanced translocation involving chromosomes 1 and 3 with a net loss of the 3q region, could result in an insertion-duplication involving chromosome 3 and 9. This seemingly unusual finding prompted further investigation which revealed that the pregnancy was achieved via IVF using both the mother's as well as related donor oocytes i.e. the maternal aunt's. Reportedly, three embryos were transferred, only one of which was derived from maternal oocyte. It is therefore plausible that the maternal aunt would be the carrier of a related rearrangement e.g. a balanced insertion. Follow up familial analyses are underway and will be discussed with the audience. This case highlights the significance of comprehensive genetic workup prior to the utilization of assisted reproductive technology, even in the absence of phenotypic anomalies in the parents.
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