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time than before. For example, the CRISpr MEdiated REarrangement (CRISMERE) strategy. deletions,
duplications, and inversions of genomic regions as large as 24.4 Mb can be obtained [44,45] , making such
studies easier than before.

If the identified genetic variant falls within a non-coding region, the challenge to understand its functional
consequence is even greater. Accurate classification of regulatory regions can be of immense help in
predicting the biological effects of noncoding genetic variants associated with particular traits and diseases.
However, determining whether a given genetic variant affects the function of a regulatory element is still
nontrivial. One example is seen with the transcription factor-encoding gene ARX in which protein-coding
mutations cause various forms of ID and epilepsy. In contrast, variations in ARX surrounding non-coding
sequences are correlated with milder forms of non-syndromic ID and autism. Using zebrafish transgenesis,
long-range regulatory domains and brain region-specific enhancers were identified that explained the
[46]
neuronal phenotypes related to the associated neuropsychiatric disease .
FROM GENES TO BIOLOGICAL PATHWAYS
With all these efforts, the biological processes involved in ID are starting to unravel. Genes related to ID
are involved in a variety of biological functions and clusters in processes such as metabolism, transporters,
[22]
nervous system development, RNA metabolism, and transcription . Examples of these functional nodes
are discussed next.

The RAS-MAPK (mitogen-activating protein kinase) and the PI3K-AKT-mTOR pathways were first
[47]
associated with cancer, but are known to be critical for synaptic plasticity and behavior . The RAS-MAPK
signaling cascade is a metabolic pathway that regulates growth factors and embryological development and
is now associated with syndromic ID such as Noonan (OMIM #163950) and Costello syndromes (OMIM
[48]
#218040) . ThePI3K-AKT-mTOR signaling cascade contributes by mediating various cellular processes
including cell proliferation and growth, and nutrient uptake. Dysregulation of this node has been identified
as a cause of several neurodevelopmental diseases, including megaloencephaly, microcephaly, autism
spectrum disorder, ID, schizophrenia and epilepsy [49,50] .

The RHO-GTPase signaling cascade is associated with a variety of cellular functions including the
morphogenesis of dendritic spines. Mutations in both regulators and effectors of the RHO GTPases (i.e.,
[51]
GDI, PAK3, ARHGEF6) have been found to underlie various forms of non-syndromic ID . Mutations in
one of the downstream effectors, the calcium/calmodulin-dependent protein kinase type II (CaMKII), have
[52]
been reported in patients with ID . Moreover, mutations in the cytosolic protein SYNGAP1 (SYNaptic
GTPase activating protein) result in a neurodevelopmental disorder termed Mental retardation-type 5
(MRD5, OMIM #612621) with a phenotype consisting of ID, motor impairments, and epilepsy. SYNGAP1
plays critical roles in synaptic development, structure, function, and plasticity and is one of the targets of
[53]
phosphorylation by CaMKII . This example serves to illustrate the power of identifying pathways towards
understanding ID biology.

Pathway convergence [54-57] could stem from the fact that the repertoire of cells affected by ID is limited
and therefore, the pathways into which ID-associated variants congregate is a reflection of the specialized
function of brain cells. However, the accurate identification of such converging pathways has the potential
to help understand brain dysfunction and pathology.

ID ASSOCIATED WITH EPIGENETIC MISREGULATION
A critical feature of the human brain that underlies cognition and the development of intellectual abilities is
the capacity of the nervous system to reorganize its connections functionally and structurally in response to