**3. Application area**

The concept of phenotype refers to the traits and features that are characteristic of a person. Thus, the phenotype includes body structures, physiological processes, but also conducts that result from the expression of the genotype in a given environment, and a specific epigenetic profile. Each individual has a unique phenotype.

Neuropsychiatric disorders tend to be classified as discrete diagnostic entities. This classifica‐ tion is limited to clinical symptoms and functioning. However, it has been suggested that these phenotypes may be arbitrary and they may encompass a heterogeneous group of subjects [41].

The concept of endophenotype was adopted in Genetics in 1966 for the study of insects, specifically grasshoppers, to indicate an internal phenotype, a behavior or conduct that did not affect the external features of the animal. In 1967 this term was used in the field of human behavior; the goal was to measure situations that were not perceptible without instruments.

In general, endophenotypes are not considered the diagnosis of the disorder per se, or the clinical characteristics observed by the physician when interviewing the patient. They could be defined by internal attributes associated with the disorder or hidden to the naked eye; they could potentially be associated with more basic phenomena and be defined by inherited quantitative traits associated with a genetic risk to a familiar disorder [42, 43].

An endophenotype would ideally have a precise biological meaning, and a more direct relationship with the action of specific genes. Therefore, its study may facilitate the identifica‐ tion of complex behaviors that are associated with genetics in the population or in an impor‐ tantfractionofit.Atthe end,this is a strategyto try tounderstandthepathologicalrole of certain genetic variants and to facilitate the identification of the mechanisms involved in disorders. Endophenotypes may be related with neurophysiological activities, neuroanatomy, neuropsy‐ chology, cognitive development (such as language and memory), or brain volume [44, 45].

Any biomarker should contribute to identify the presence of a given disorder, but it may be influenced by the health status of the person or by the effects of environmental factors. In order to be considered as an endophenotype, the biomarker is expected to be heritable, to cosegregate with the disorder, and as such, to be influenced by the genetic component of the disorder [46]. Endophentoypes have sometimes been referred to as intermediate phenotypes, but some authors do not agree on the indistinctive use of these two terms. An intermediate phenotype could be considered as a subclinical picture of psychopathology [47].

Different endophenotypes may be associated with ASD. Ideally, each one should:

**a.** Cosegregate with the disorder.

errors in DNA methylation during spermatogenesis may affect the next generations. Recently, it was found in a mouse model that older fathers had a significant decrease in methylation in genomic regions associated with the control of transcription. Indeed, the expression of developmental genes implicated in ASD was dysregulated in the offspring of old fathers [31].

Other non genetic factors that have been associated with ASD include maternal use of certain substances during pregnancy, such as valproic acid, ethanol, thalidomide or misoprostol; low birth weight (or intrauterine growth retardation), congenital rubella and other infections, as well as cerebral palsy [32-38]. Environmental insults may increase the risk to ASD in genetically sensitive individuals, possibly by promoting cellular oxidative stress, and adaptive responses that could include reduced methylation activity, which is the most common epigenetic mechanism. Interestingly, the 15q11-q13 chromosomal region is subject to methylationdependent genomic imprinting [39]; in addition, GABAergic genes in the same region, GABRB3, GABRA5, and GABRG3, were found to be epigenetically dysregulated in a subset

Despite important advances in molecular genetics, the complete spectrum of the genetic component of ASD is still largely unresolved. There are many possible reasons for this partial lack of success. Among them, the complexity of the Central Nervous System, the relatively unique set of risk factors in each patient, which includes the combined effect of genetic (long/ short, common, rare, and/or de novo sequences), and the interaction with environmental and epigenetic components. Furthermore, the possibility of genetic loci affecting two or more distinct traits or phenotypes (pleiotropy), and an incomplete penetrance (lack of clinical symptoms in individuals who carry risk alleles) also complicate the genetic studies of ASD.

The core symptoms of ASD, differences in intellectual and language abilities, and comorbidity, among other characteristics help highlight the presence of clinical heterogeneity in ASD. Knowledge about variability of genetic, environmental, and epigenetic factors in these disorders, as well as the presence of clinical heterogeneity, has propelled the search for more homogenous groups of patients through the study of potential endophenotypes. They may contribute to facilitate the identification of genetic risk factors and basic molecular mechanisms

The concept of phenotype refers to the traits and features that are characteristic of a person. Thus, the phenotype includes body structures, physiological processes, but also conducts that result from the expression of the genotype in a given environment, and a specific epigenetic

of ASD patients [40].

involved in ASD.

**3. Application area**

profile. Each individual has a unique phenotype.

**2. Problem statement**

354 Autism Spectrum Disorder - Recent Advances


**i.** Be identified for genetically related disorders [48-51].

Thus far, the identification of endophenotypes has been successful in several fields of Medi‐ cine. Endophenotypes were useful in the identification of genes for QT syndrome, idiopatic hemochromatosis, juvenile myoclonic epilepsy, and familial adenomatous intestinal polypo‐ sis. Biochemical assays, physiological measures and challenges contribute as primary evidence of pathology in the detection of increased risk to diabetes, hypercholesterolemia, obesity, hypertension, and osteoporosis [48, 52, 53]. Furthermore, different endophenotypes have been proposed for neuropsychiatric disorders.
