Genetic Testing For Autism Spectrum Disorders And Developmental Conditions

Genetic Testing For Autism Spectrum Disorders And Developmental Conditions – Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders, affecting approximately 1 in 59 children. ASD is highly genetic and can be caused by both inherited and de novo genetic variants. both. Over the past decade, hundreds of genes have been identified that contribute to the severe deficits in communication, social cognition, and behavior that patients often experience. However, these are only 10-20% of ASD cases, and patients with different types of pathology can be diagnosed at different levels of the spectrum. In this review, we will describe the genetic profile of ASD and discuss how genetic modifiers such as copy number variations, single nucleotide polymorphisms, and epigenetic changes likely play an important role. Visual processing in ASD patients. We also consider how genetic modifiers can alter complex signaling pathways and lead to impaired neural circuit development. Finally, we review sex-related changes and clinical implications. Further understanding of these mechanisms is important for both understanding ASD and developing new treatments.

Autism was first described by Kanner (1943) in a detailed report on 11 children with abnormal behavior. Commonly appealing symptoms such as inappropriate simplification of language, indifference to others, and interesting interests are clearly visible when reading Kanner’s comprehensive patient history. Twenty-three years later, the first epidemiological study of autism estimated the prevalence at 4.5 per 10,000 people. Estimates rise significantly to 1 in 59 individuals affected, with at least three times more men than women (Loomes et al., 2017). This dramatic increase in prevalence can be partially attributed to the increased awareness and development of the diagnostic and statistical criteria for mental disorders (DSM), from a form of childhood schizophrenia in 1952, to a basic analysis covering a wide range of disorders today (Zeldovich , 2018). The changing landscape of diagnostic criteria makes it difficult to estimate the actual increase in prevalence.

Genetic Testing For Autism Spectrum Disorders And Developmental Conditions

According to the current DSM-5 criteria, only two main characteristics make the diagnosis of autism spectrum disorder (ASD): (1) persistently decreased social communication and social interaction in many areas; and (2) limited, repetitive patterns of behavior, interests, or activities (Lai et al., 2014). Because of the broad nature of these definitions, the diagnosis of ASD often occurs with other conditions. Motor abnormalities (79%), gastrointestinal problems (up to 70%), epilepsy (up to 30%), intellectual disability (45%), sleep disorders (50-80%) are common examples ( Lai et al., 2014). Language disorders occur frequently and are even included in the DSM-IV criteria.

Genomics In Neurodevelopmental Disorders: An Avenue To Personalized Medicine

Since the diagnosis of autism, the medical and scientific community has invested considerable effort in identifying risk factors and etiology. In Kanner’s original analysis, he made the unfortunate observation that in addition to patients with brilliant parents, “Another fact stands out. In the whole group, there are very warm-hearted fathers and mother. small” (Kanner, 1943) . Fortunately, the “refrigerator mother” theory of autism was quickly debunked. ASD is now understood to be a complex interplay between genetics and environment, with heritability estimates ranging from 40 to 80% (Chaste and Leboyer, 2012). Numerous genetic studies have revealed hundreds of genes that have been linked to autism. Epidemiological studies have begun to identify environmental factors that may contribute to risk, but much remains to be understood about how they interact with genetic predisposition to contribute to ASD etiology. .

As is often the case in complex diseases, individuals with different pathogen variants may have different phenotypes. For example, people with a copy of 15q closely range from unaffected to severely impaired (Cook et al., 1997; Bolton et al., 2001). Genetic modifiers – factors that change the expression of other genes – are likely to exist when individuals with pathogenic variants are at opposite ends of the spectrum. In this review, we will discuss what is currently known to be the genetic profile of ASD, and then look at possible changes including copy number variations (CNVs), duplicate mutations, and epigenetic effects. , and gender-related effects.

After the classification of autism by Kanner, research efforts were made to determine the etiology of the disease. Although it was initially thought to be environmental in origin, improved understanding of the role of genetics in human health suggested otherwise. In 1977, Folstein and Rutter (1977) conducted a twin study and observed that the incidence of siblings was 50 × higher than the average. They found that monozygotic twins were more likely to share the disease than dizygotic twins, suggesting a genetic influence. Bayley et al. (1995) supported this finding, documenting a 60% concordance in monozygotic twins compared to conjoined dizygotic pairs. In addition, a child’s risk of developing ASD has been found to be proportional to the percentage of the genome they share with an affected sibling or parent (Constantino et al., 2010; Risch et al., 2014; Sandin et al., 2014 . ). At the turn of the century, ASD was established to have a genetic component, although the genes involved remained a mystery.

Autism Spectrum Disorder (asd) + Young People

Early karyotype studies documenting chromosomal abnormalities began to shed light on the regions of the genome involved (Gillberg and Wahlström, 1985). Additional susceptibility screens for chromosomal regions 7q, 1p, 3q, 16p, and 15q Liu et al., 2001; Auranen et al., 2002; Lamb et al., 2002; Shao et al., 2003; Risch et al., 2014). However, to investigate the resolution at the gene level, previous studies had to use the candidate method. Hypothesized targets include genes suspected of being chromosomal regions with an important role in neurodevelopment, such as the homeobox (Hox) family or Wnt genes. Not surprisingly, many previous studies using this method have been inconclusive (Krebs et al., 2002; Lamb et al., 2002; Talebizadeh et al., 2002; Zhang et al., 2002). In 2001, the candidate method achieved moderate success with results supporting reelin (RELN), homeobox (Arx), methyl-CpG binding protein 2 (MeCP2), neuroligin 3 (NLGN3), neuroligin 4 (NLGN4), tuberous sclerosis 2 (TSC2), and ubiquitin protein ligase E3A (UBE3A) in the involvement of ASD etiology (Persico et al., 2001; Strømme et al., 2002; Carney et al., 2003; Jamain et al., 2003; Serajee et al. et al., 2003). et al., 2003; Jiang et al., 2004).

In the early 2000s, the advent of high-throughput sequencing revolutionized genetic research and allowed researchers to study ASD on a genome-wide level. Sequencing technology quickly confirmed that the etiology of ASD is highly heterogeneous, with very few identical pathogenic variants accounting for a significant percentage of distressed individuals. It is now known that the common case is more of a product of vulnerability-increasing variability. Only a few of the disorders associated with ASD have a monogenic cause, such as Rett syndrome, fragile X syndrome, tuberous sclerosis, and Schuurs-Hoeijmakers syndrome (Artuso et al., 2011; Stern et al., 2017; Woodbury-Smith and Scherer, 2018). Dozens of large-scale genetic studies have since been performed on ASD patients and their families, resulting in the discovery of hundreds of risk genes. Although these proteins have different functions, most of the hits that can be made come from two groups of proteins: those involved in synapse formation, and those involved in the regulation of transcription and chromatin remodeling pathways (De Rubeis et al., 2014).

Synapse-related risk genes include those encoding cell adhesion proteins such as neuroligins, neurexins, and cadherins; the cycling proteins synapsin-1 (SYN1) and synapsin-2 (SYN2); ion transport proteins such as sodium voltage-gated channel alpha subunit 2 (SCN2A), voltage-gated calcium channel subunit alpha1 E (CACNA1E), voltage-gated calcium channel auxiliary subunit beta 2 (CACNB2), potassium voltage-gated channel lower Q members 3 and 5 (KCNQ3 and KCNQ5), potassium voltage-gated channel subfamily D member 2 (KCND2), glutamate receptor signaling protein SH3 and multiple ankyrin repeat domains 3 (SHANK3), synaptic Ras GTPase activating protein 1 (SYNGAP1), and gamma – aminobutyric acid type A receptor gamma3 subunit (GABRG3) (Jamain et al., 2003; Durand et al., 2012; Schmunk and Gargus, 2013; Giovedí et al., 2014; Stessman et al., 2017). In vivo data support the impact of synapse pathology and abnormal neural network development in ASD.

Causes Of Autism

Additional susceptibility to influence the transcription of other proteins through different mechanisms. For example, several studies have found increased de novo mutations in regulatory elements that are at risk for ASD in patients (Turner et al., 2016, 2017; Short et al., 2018). A broad spectrum of susceptibility genes affecting chromatin remodeling pathways include MeCP2, UBE3A, chromodomain helicase DNA binding protein 8 (CHD8), activity-dependent neuroprotector homeobox (ADNP), transposable elements from available ZNF domain (POGZ), soft X soft. brain retardation protein (FMRP), and RNA binding box forkhead (RBFOX) genes (Carney et al., 2003, p. 2; Samaco et al., 2005; De Rubeis et al., 2014; Stessman et al., 2017 ; Tran et al., 2019). These pathogenic variants have the potential to cause widespread effects. For example, Tran et al. (2019) recently showed that FMRP and fragile X-related protein 1 (FXRP1) mutations can cause abnormal RNA-editing enzyme activity, leading to a global adenosine-to-inosine hypoediting bias in ASD brains. . The different types of consequences are discussed further in the section on epigenetics.

Pathogenic variants are generally thought to be familial/inherited in each cell

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