Complex genomic rearrangements in rare brain disorders : genetic architecture and molecular consequences

Abstract

Structural variants (SVs) within the genome, such as deletions, duplications, inversions, and translocations, are common but underappreciated causes of rare diseases. Complex genomic rearrangements involving two or more SVs in cis are incredibly challenging to detect. The genome is analyzed using sequencing technologies to understand such events and their underlying mechanisms. Patient-specific cell models help deepen the understanding of the mechanism causing disease.

Paper I investigated patient-derived neural cells from an individual with a ring chromosome 21 and partial monosomy 21, and with two individuals with trisomy 21. RNA-Seq revealed 13.7% differential expression genome-wide in the ring 21 cells. When comparing the ring 21 cells to trisomy 21 lines, approximately 8.8% of all genes showed contrasting expression patterns, with some genes being upregulated in cells with trisomy 21 while downregulated in ring 21 cells and vice versa.

Paper II utilized Nanopore long-read genome sequencing to map a challenging balanced translocation between the short arm of chromosome 17 and the centromere of chromosome 19. The event had occurred de novo in an individual with autism, congenital cataract, epilepsy, and osteoporosis. A candidate gene, MINK1, was disrupted, leading to reduced RNA levels of MINK1 in patient-derived neural cells shown with RNA-Seq and qPCR.

Paper III focused on three individuals with developmental delay and complex chromosomal rearrangements spanning chromosome 21. Following short-read and longread genome sequencing and optical genome mapping, we identified 15, 8, and 26 breakpoints in each patient. Using the T2T-CHM13 assembly, we showed that the satellite region of 21p was involved in all three events.

Paper IV examined three individuals with CTNND2 disruptions. Using patient-derived neural cells and brain organoids, we demonstrated that CTNND2 plays a crucial role in neurogenesis and cell proliferation, mainly through the WNT signaling pathway. When this pathway was not externally stimulated, it partially rescued the cellular and transcriptional abnormalities.