Stable transmission of an unbalanced chromosome 21 derived from chromoanasynthesis in a patient with a likely pathogenic variant.

Background: Complex genomic structural variations, involving chromoanagenesis, have been implicated in multiple congenital anomalies and abnormal neurodevelopment. Familial inheritance of complex chromosomal structural alteration resulting from germline chromoanagenesis-type mechanisms are limited.

Case Presentation: We report a two-year eleven-month old male presenting with epilepsy, ataxia and dysmorphic features of unknown etiology. Chromosomal microarray identified a complex unbalanced rearrangement involving chromosome 21. G-banding and FISH for targeted regions of chromosome 21 revealed that the copy number imbalances were limited to gains dispersed throughout the long arm of chromosome 21, characteristic of a chromosome derived from chromoanagenesis. Family studies showed that the unbalanced chromosome had been stably inherited, as it was present in both his healthy mother and maternal grandfather. Further molecular testing for non-syndromic intellectual disability genes found a likely pathogenic mutation in (NM_006772.2:c.3722_3723del).

Conclusions: This study indicates that complex rearrangements involving an unbalanced chromosome derived from chromoanasynthesis can be familial and should be not be presumed pathogenic.