The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Abstract

Despite their clinical significance, characterization of balanced chromosomal abnormalities (BCAs) has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and revealed complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. This study proposes that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements, and provides insight into novel pathogenic mechanisms such as altered regulation due to changes in chromosome topology.

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

“…While much of the focus in SV detection from WGS has concentrated on CNVs alone, we previously demonstrated the importance of translocations, inversions, and inversion-mediated complex SVs in ASD and congenital anomalies 27–29 . We thus characterized all classes of SV accessible to short-read WGS.…”

When TADs go bad: chromatin structure and nuclear organisation in human disease

“…The extent of such disruptions in human developmental disease cases is largely unknown, but recent studies have shown that pathogenic human structural variants (SVs) overlap the boundary regions of TADs, including duplications at the SOX9 locus 19 and deletions at the MEF2C locus 20 in certain cases of developmental disorders. Furthermore, SVs disrupting an orthologous TAD boundary (found in human and mouse nuclear organisation) can give rise to the same developmental defect 19 , suggesting a conserved functional role.…”

Genome sequencing in cytogenetics: Comparison of short‐read and linked‐read approaches for germline structural variant detection and characterization

“…The widespread development of next‐generation sequencing (NGS) technologies now enables SV detection in whole genome data at base‐pair resolution (Dong et al, ; Liang et al, ; Talkowski et al, ). Recent studies highlighted that ABCRs are more complex than expected, with more breakpoints and cryptic deletions/duplications than expected (Collins et al, ; Redin et al, ). They confirmed that ABCRs can lead to gene disruption and/or positional effect, and explain some phenotypes, such as MCA/ID for example (Nilsson et al, ; Redin et al, ; Schluth‐Bolard et al, ).…”