Breakpoint analysis for cytogenetically balanced translocation revealed unexpected complex structural abnormalities and suggested the position effect for MEF2C

Abstract

AbstractMany disease‐causing genes have been identified by determining the breakpoints of balanced chromosomal translocations. Recent progress in genomic analysis has accelerated the analysis of chromosomal translocation‐breakpoints at the nucleotide level. Using a long‐read whole‐genome sequence, we analyzed the breakpoints of the cytogenetically balanced chromosomal translocation t(5;15)(q21;26.3), which was confirmed to be of de novo origin, in a patient with a neurodevelopmental disorder. The results showed complex rearrangements with seven fragments consisting of five breakpoint‐junctions (BJs). Four of the five BJs showed microhomologies of 1–3‐bp, and only one BJ displayed a signature of blunt‐end ligation, indicating chromothripsis as the underlying mechanism. Although the BJs did not disrupt any disease‐causing gene, the clinical features of the patient were compatible with MEF2C haploinsufficiency syndrome. Complex rearrangements were located approximately 2.5‐Mb downstream of MEF2C. Therefore, position effects were considered the mechanism of the occurrence of MEF2C haploinsufficiency syndrome.