Chromoanagenesis of chromosome 22 in a subject with obesity and borderline cognitive performance

Chromoanagenesis events consist of complex chromosome rearrangements with multiple breakpoints in one or few chromosomes. Mechanisms of chromoanagenesis are split into three major groups: chromothripsis, chromoanasynthesis and chromoplexy. This study aims to delineate a chromoanagenesis event at the level of chromosome 22 in an individual showing obesity and borderline cognitive performance as major disturbances. The proband and his parents were subjected to conventional karyotyping, CGH array and whole genomic sequencing (WGS). By conventional karyotyping a "de novo" pericentric inversion of chromosome 22 was identified. CGH array identified several imbalances (either deletions or duplications) in the long arm of chromosome 22; the largest is a 4.5 Mb duplication at 22q12.1-22q1.3. The detection of extensive duplications would suggest the occurrence of a chromoanasynthesis event. WGS, in addition to the structural alterations identified by karyotyping and CGH array, revealed two translocations from chromosome 22 to chromosomes 6 and 21 as well as a heterozygous pathogenetic variant of ALMS1 gene; the latter could have contributed to the obesity of our patient. The pericentric inversion induces loss of initial part of TCF20 gene including the 5' regulatory region and the first, noncoding, exon. Heterozygous loss-of-function mutations of TCF20 gene have been found in patients with autism spectrum disorder or intellectual disability, some of them presenting obesity. It is, therefore, possible that disruption of TCF20 gene structure would contribute to a fraction of the patient's phenotype.