Large Clinically Consequential Imbalances Detected at the Breakpoints of Apparently Balanced and Inherited Chromosome Rearrangements

2010-09-02 21:55:14

The Journal of Molecular Diagnostics; 2010 Sept; 12(5):725-29

Sarah T. South, Lyndsey Rector, Emily Aston, Leslie Rowe, and Samuel P. Yang


Numerous studies have shown that de novo apparently balanced translocations associated with an abnormal phenotype are often more complex than appreciated at the chromosome banding level. These translocations are therefore more likely to result in disruption of copy number sensitive loci, more likely to have a cryptic imbalance at or near one of the translocation breakpoints, or have cryptic imbalances elsewhere in the genome.

However, most of these studies have focused on de novo apparently balanced rearrangements and have not examined inherited rearrangements. Because balanced translocations occur in approximately 1:500 individuals and the majority are inherited (1:2000 balanced rearrangements are de novo), it is easy to conclude that a phenotypic abnormality and a balanced translocation can occur coincidentally in an individual, especially when that same rearrangement is found in a normal related individual, such as a parent.

It is also recognized that a de novo balanced rearrangement does increase the risk for a serious congenital anomaly to approximately 6.7%. This increased risk is usually thought to be due to a disruption of genes or regulatory elements. Many examples of this exist in the literature and have even led to the identification of the causative gene for numerous Mendelian conditions.

Therefore, when an apparently balanced rearrangement is identified in a child with phenotypic abnormalities, parental studies are often recommended as the next step as this is necessary for recurrence risk counseling and is useful for determining the clinical significance of the rearrangement. If the same balanced rearrangement is found in a normal parent, an alternative cause of the child's phenotypic abnormalities is sought.

We present two cases that challenge the algorithm of parental studies being the next step in follow-up as well as the assumption that an identical banding pattern in a normal parent can be interpreted as evidence that the rearrangement is coincidental to the child's abnormal phenotype.

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