Abstract:
The sheer number of gene variants and the extent of the observed clinical and molecular heterogeneity recorded in neuropsychiatric disorders (NPDs) could be due to the magnified downstream
effects initiated by a smaller group of genomic higher-order alterations in response to endogenous
or environmental stress. Chromosomal common fragile sites (CFS) are functionally linked with
microRNAs, gene copy number variants (CNVs), sub-microscopic deletions and duplications of
DNA, rare single-nucleotide variants (SNVs/SNPs), and small insertions/deletions (indels), as well
as chromosomal translocations, gene duplications, altered methylation, microRNA and L1 transposon
activity, and 3-D chromosomal topology characteristics. These genomic structural features have been
linked with various NPDs in mostly isolated reports and have usually only been viewed as areas
harboring potential candidate genes of interest. The suggestion to use a higher level entry point (the
‘fragilome’ and associated features) activated by a central mechanism (‘stress’) for studying NPD
genetics has the potential to unify the existing vast number of different observations in this field. This
approach may explain the continuum of gene findings distributed between affected and unaffected
individuals, the clustering of NPD phenotypes and overlapping comorbidities, the extensive clinical
and molecular heterogeneity, and the association with certain other medical disorders.
