Chromothripsis is defined as localised shattering and reshuffling of chromosome fragments due to a catastrophic event and is a cancer hallmark. However, chromothripsis in constitutional germline cases is rare. Its degree of contribution to human disease is not well characterised. Cancer chromothripsis typically involves one chromosome shattering and reshuffling of clustered chromosome regions; more chromosomes may be involved with an oscillating balanced–unbalanced pattern in congenital chromothripsis (ConC). Microarray testing, performed for congenital anomalies and developmental delay, will detect copy number variants as a result of chromothripsis but will not identify the balanced re-assembly typically seen in ConC. Routine karyotyping (local case) was requested for a child with multiple congenital anomalies, neurodevelopmental delay and known deletions of 1p31.3, 1p31.1 and 6q21q22.1 of uncertain significance. G-banded karyotyping showed complex structural rearrangements involving chromosomes 1, 6 and 7: a possible insertion of 1p31->p31.3 into 7q31.3 with inversion of 7q22->q31.3, and three-way translocation between 1p31.1, 7q31.3 and 6q16.3. Whole genome sequencing showed at least nine discernible breakpoints characterising ConC and no explanatory sequence variants. This case illustrates the complexity of chromosomal abnormalities and the need for conventional cytogenetics, adds to literature on incidence of ConC in human disease, and refutes the dogma that chromothripsis is limited to cancer.
Estrella et al. (Sun,) studied this question.