Page 47 - Read Online

Marti et al. J Transl Genet Genom 2020;4:104-13 I http://dx.doi.org/10.20517/jtgg.2020.10 Page 105

cognitive function is a core clinical feature of neurodevelopmental disorders (NDDs), which comprise
a group of developmental disorders leading to brain dysfunction. NDDs include global developmental
delay, intellectual disability (ID), schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity
disorder, bipolar disorder, and epilepsy. Studies on NDDs have revealed that cognitive disorders are
[2]
[3,4]
complex, usually polygenic , and phenotypically and genetically heterogeneous . ID is characterized
by significant limitations in both intellectual functioning and in adaptive behavior including conceptual,
[5]
social, and practical adaptive skills .
[6-8]
ID originates during the developmental period and has an incidence of ~2% in the population . Although
ID can be caused by environmental factors such as maternal alcohol abuse during pregnancy, infections,
birth complications and extreme malnutrition, genetic factors are now known to have an important
role in its etiology, accounting for the majority of cases. ID is the most common reason for referral
to genetic services and recent technological advances have allowed genetic diagnoses to be obtained
for a substantial portion of affected individuals. The combination of novel technologies and increased
biological understanding is rapidly increasing the diagnostic yield of genetic tests in ID. The introduction
of chromosome array analysis (comparative genomic hybridization, CGH) has allowed the genome-wide
detection of chromosomal aberrations, while exome sequencing (WES) and more recently whole genome
sequencing (WGS) have enabled testing of all genes simultaneously in a single test. Currently, WGS is
[9]
becoming the first-tier diagnostic test, which also allows for the detection of chromosomal aberrations .
These are impressive advancements that have important ramifications for both treatment and prognosis.
[10]
A specific diagnosis also provides both psychological and social benefits for the family , including
information about the risk of recurrence in future pregnancies and the options of prenatal diagnosis
and pre-implantation genetic testing. As of December 2019, on the Online Mendelian Inheritance in
Man website (OMIM, https://omim.org/), there are more than 1300 single genes associated with ID,
highlighting the complexities of brain development and the consequent, extreme genetic heterogeneity
of ID. These genes are all related to a variety of cellular functions and molecular processes. On top of the
functional diversity of ID associated genes, there is a myriad of genetic variants within the same gene loci
with different pathological consequences, ranging from benign (no identifiable phenotypic consequences)
to clearly pathogenic (associated with extreme phenotypic outcomes). Identification of new genes and
genetic variants related to ID and improved understanding of the biological functions associated with these
mutations are now critical.

GENOMIC ADVANCES RELATED TO ID
[11]
During the late twentieth century, twin studies showed that ID has a strong heritable component .
However, only in the beginning of the new millennium, with the advent of Next Generation- or massive-
Sequencing technologies, has determination of the underlying genetic cause of ID, as well as many other
congenital diseases, become possible . An accurate molecular diagnosis is essential for the optimization
[12]
[13]
of clinical management and the institution of appropriate surveillance and prevention programs . De novo
mutations account for at least 30%, and possibly as much as 60%, of ID cases, with diagnostic efficiency in
[14]
clinical practice around 25%-30% . This low diagnostic yield begets the question of what the causes of ID
are in the remaining 75% of patients. Genetic and phenotypic variability, and the non-specific nature of the
phenotype makes accurate genetic diagnosis in the majority of children with ID a very challenging task.
In cases where no obvious causes are found, the differential diagnosis can include hundreds of rare genetic
disorders, leading to hundreds of potentially involved genes, with both single nucleotide (SNVs) and
copy-number variants (CNVs) putatively contributing to disease development. In this context, different
molecular techniques for diagnosis coexist with each having particular pros and cons [15-17] .

Array based CGH was the first choice for diagnosing ID ten years ago, with a two-fold increase in
diagnostic yield compared with karyotype analysis . CGH allowed precise identification of CNVs as small
[15]