Rare or Overlooked? Structural Disruption of Regulatory Domains in Human Neurocristopathies

Abstract

In the last few years, the role of non-coding regulatory elements and their involvement in human disease have received great attention. Among the non-coding regulatory sequences, enhancers are particularly important for the proper establishment of cell type-specific gene-expression programs. Furthermore, the disruption of enhancers can lead to human disease through two main mechanisms: (i) Mutations or copy number variants can directly alter the enhancer sequences and thereby affect expression of their target genes; (ii) structural variants can provoke changes in 3-D chromatin organization that alter neither the enhancers nor their target genes, but rather the physical communication between them. In this review, these pathomechanisms are mostly discussed in the context of neurocristopathies, congenital disorders caused by defects that occur during neural crest development. We highlight why, due to its contribution to multiple tissues and organs, the neural crest represents an important, yet understudied, cell type involved in multiple congenital disorders. Moreover, we discuss currently available resources and experimental models for the study of human neurocristopathies. Last, we provide some practical guidelines that can be followed when investigating human neurocristopathies caused by structural variants. Importantly, these guidelines can be useful not only to uncover the etiology of human neurocristopathies, but also of other human congenital disorders in which enhancer disruption is involved.

Chromoanagenesis Event Underlies a de novo Pericentric and Multiple Paracentric Inversions in a Single Chromosome Causing Coffin–Siris Syndrome

“…The pathogenetic consequence of this type of structural variant may result from a breakpoint occurring within the exon of a gene or in an intragenic fashion between exons (Feuk, 2010); the end result is a gene split apart disrupting its function (Lakich et al, 1993). More cryptically, inversions may disrupt enhancer or topologically associated domains surrounding a gene, causing no change in the gene itself but leading to a pathogenic consequence through change in gene expression, a potential position effect, or other perturbations of gene regulation (Lupianez et al, 2015;Kraft et al, 2019;Sanchez-Gaya et al, 2020).…”

Hit-and-run silencing of endogenous DUX4 by targeting DNA hypomethylation on D4Z4 repeats in facioscapulohumeral muscular dystrophy

“…Hit-and-run off-target silencing, if it happens, could also possibly cause robust and long-term impacts, which should be avoided in terms of safety in clinical situations. Moreover, intergenic regulatory regions have recently been proven to have pathogenic potentials due to disrupted fine tuning, especially in humans 62,63 . In this sense, in the context of future clinical use, higher coverage methods such as bisulfite high-throughput sequencing-based off-target analysis can be applied to strictly evaluate off-target risks in a sustainable manner to allow for future re-analysis for de novo identified naive sites.…”

The phenotype of 15 cases with rare 8q24.13‐q24.3 deletions–A new syndrome or still an enigma?

“…Furthermore, there is a possibility of epigenetic effects, for instance those caused by impairment of the interactions between topologically associating domains, altering activation or suppression of gene expression (Sanchez‐Gaya et al, 2020). In addition, even gene‐depleted loci or “gene deserts” might encompass control or protein binding regions.…”