Finding Recessive Genes For Autism Spectrum Disorders
Christopher Walsh and his colleagues at Boston Childrens Hospital have been studying the genetics of autism by analyzing inherited recessive mutations in consanguineous families those in which the parents are related to each other .
Inherited genetic diseases in the children of such families are often caused by recessive mutations present in a recent ancestor that are transmitted through each parent, resulting in the child inheriting two copies of the mutation. These mutations are transmitted along with large blocks of the surrounding genome.
Using this approach, Walshs group identified several strong candidate genes associated with autism1. They showed that the identified mutations affect the function of the protein produced by the candidate gene. Several of the candidate genes were previously associated with more severe neurologic disruption, including metabolic disorders and brain malformation syndromes.
Walsh found that mutations that completely disrupt these genes tend to cause severe disorders, whereas mutations that only partially impair gene function tend to result in less severe autism spectrum disorders. This finding has important implications for both the diagnostic workup of children with autism and the development of treatments.
Study Links Gene To Inherited Form Of Autism
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Inherited mutations in a gene called ACTL6B lead to autism, epilepsy and intellectual disability, according to a new study1.
The mutations are recessive, which means that they lead to autism only if a person inherits them in both copies of the gene one from each parent, who are silent carriers. Most other mutations implicated in autism are spontaneous, or de novo, mutations, which are not inherited.
The study suggests that recessive mutations in ACTL6B could be a relatively common cause of autism, says co-lead researcher Joseph Gleeson, professor of neurosciences and pediatrics at the University of California, San Diego.
ACTL6B helps to control the expression of other genes in brain cells by encoding part of a protein complex called BAF. This complex tightens and loosens chromatin, the bundle of DNA and protein crammed inside a cells nucleus, during transcription. Scientists have linked autism to mutations in many other chromatin regulation genes including several that encode other parts of the BAF complex.
ACTL6B mutations have previously been associated with neurodevelopmental conditions, but the new study makes a strong case that they are tied to autism, says Gaia Novarino, professor of neuroscience at the Institute of Science and Technology in Klosterneuburg, Austria, who was not involved in the study.
Clinical Heterogeneity Potential Endophenotypes And Quantitative Trait Analysis
ASD itself also exhibits significant clinical heterogeneity. Recent advances in diagnosis, such as the autism diagnostic inventory and autism diagnostic observation schedule may reduce uncertainty in diagnosis, but considerable variability remains. Symptoms and signs, rather than etiologies, comprise psychiatric syndromes such as autism, as well as other medical syndromes, including diabetes and inflammatory bowel disease. Each gene may make a somewhat different contribution to the disorder, with gene X important in social cognition and gene Y important in language acquisition. When clustering of risk alleles reaches a certain threshold, an individual is at increased risk of developing the disorder. A subthreshold number of risk alleles may result in the broader autism phenotype identified in family members of patients with autism.,
Initial analyses in ASD have primarily considered the endophenotype of general language impairment. A number of other potential quantitative traits would be of particular interest in autism, including most prominently head circumference and whole blood serotonin, but also several others: level of intellectual functioning, degree of social or communication impairment, presence of seizure disorder, dysphmorphology, savant abilities, and restrictive and repetitive behaviors.
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Protein And Mrna Approaches
Molecular methodology is now being applied in postmortem studies of autism. These studies have tremendous potential, but initial findings may implicate a different distribution of neuronal types, numbers, and size, rather than implicating particular genes or protein systems in the pathophysiology of disease. Crosstalk between molecular pathology studies and ongoing molecular genetic investigation is crucial. For example, the genetic association at GABRB3 sparked interest in the GABA system in postmortem studies, including evidence that GABAA receptor binding is reduced., As protein and mRNA studies using microarrays and other novel approaches continue, postmortem work will generate new candidate genes for study and clarify the role of reported gene associations.
Investigators have followed three approaches in examining areas of the brain with structural abnormalities in autism. The first approach is to consider important proteins within neurotransmitter systems, including the acetylcholine system,, the glutamate system, and the GABA system,, The second approach is to consider proteins that control neuronal death, due to the finding of macrocephaly in some patients., , The last approach is to consider peptides thought to be important in neuronal migration and synaptic development., , Initial findings are promising, but additional work including immunohistochemistry may be necessary to accurately compare protein binding in relation to neuronal location and morphology.
Identification Of Candidate Asd Risk Genes
Following the classification of autism by Kanner, research efforts were undertaken to determine the disease etiology. Though it was initially assumed to be of environmental origin, an improved understanding of the role of genetics in human health soon suggested otherwise. In 1977, Folstein and Rutter conducted twin studies upon the observation that incidence among siblings was 50× higher than average. They found that monozygotic twins were more likely to share a diagnosis than dizygotic twins, suggesting a genetic influence. Bailey et al. supported this finding, documenting 60% concordance for monozygotic twins versus no concordant dizygotic pairs. In addition, risk of a child having ASD was found to be proportional to the percentage of the genome they shared with an affected sibling or parent . By the turn of the century, ASD was established to have some genetic component, though which genes were involved remained a mystery.
Somatic Mosaicism and ASD Risk
CNVs Contribute to ASD Susceptibility
Epigenetic Regulation and ASD
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Looking At My Family Line There Really Anyone Else That Has A Class 3 Underbite Like Me
Autosomal recessive diseases are genetic diseases that are passed to a child by both parents’ chromosomes. Autism spectrum disorder is a condition that appears very early in childhood development, varies in severity, and is characterized by impaired social skills, communication problems, and repetitive behaviors. Considered as a genetic condition, autism is too complex to be either dominant or recessive. In general, ad is a degenerative disease of the. This happens even when the matching gene from the other parent is normal. I asked genetics counselor kim barr of kaiser permanente to answer this and other questions about the genetics of autism and. Autosomal dominant means one copy of the abnormal gene from only one parent or in each cell is sufficient to cause the disorder or disease. Previous research suggests autism has a genetic basis, but so far, no single gene has been located that causes the disease in the general population. Huntington’s disease is a common example of an autosomal dominant genetic disorder. Heterozygotes are generally believed to be â¦ In others, the autosomal dominant condition may result from a new mutation in the gene and occur in. Autosomal dominant peo is inherited in an autosomal dominant manner. This is in contrast to a recessive disorder, where two copies of the mutation are needed to cause the disease.
Autosomal recessive diseases are genetic diseases that are passed to a child by both parents’ chromosomes.
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Annotation And Identification Of Inherited Variants
Genetic data in VCF format , and the corresponding phenotypic information were downloaded from the SFARI Base . Only coding variants with sequencing depth > 20, genotype quality > 50, and call rate > 0.9 were retained for further analysis. Quad samples containing a proband, an unaffected sibling, and their unaffected parents were analyzed. Informed consent was provided in the original study . Comprehensive annotation of all variants was performed by ANNOVAR and VarCards , as previously described . Annotation included gene regions, amino acid alterations, mutation effects, GenBank mRNA accession numbers, and minor allele frequencies in the Genome Aggregation Database . All coding variants were classified into five functional categories: PTVs, including alternative splice variants , stop-gain and stop-loss single-nucleotide variants, and frameshift indels Dmis variants with ReVe scores> 0.7 tolerated missense variants with ReVe scores0.7 synonymous variants and non-frameshift indels.
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Comprehensive Autism Spectrum Disorders Panel
Autism spectrum disorders are a group of complex disorders of brain development characterized by difficulties in social interaction, verbal and nonverbal communication, and a restricted set of activities and/or interests. By most recent estimates, ASD effects approximately 1 in 59 children and is four times more likely to be diagnosed in boys than girls. Signs begin early in childhood, with developmental delays in social interaction and language present before 3 years of age, and the associated challenges last throughout a persons life. In some cases, autism is part of a more complex genetic syndrome with other characteristics, although it can also be isolated. It is estimated that at least 10% of individuals with ASD also develop epilepsy, with a higher prevalence in females and in syndromic cases.
The Comprehensive Autism Spectrum Disorders Panel includes 228 genes that are associated with both syndromic and non-syndromic causes of autism spectrum disorders . The Comprehensive ASD Panel is recommended if a specific underlying syndrome is not suspected. For patients with a suspected syndrome or disorder, please consider single gene sequencing or associated subpanels prior to ordering the comprehensive panel. The disorders included in this panel may be inherited in an autosomal dominant , autosomal recessive , or X-linked manner.
The Genetics Of Rett Syndrome
Two gene mutations are believed to cause Rett syndrome. The first, and most common, is a mutation of the MECP2 gene. Further research has demonstrated that a mutation of the CDKL5 gene is also present in many RS patients. Both of these genes reside in the X chromosome. Both genes are responsible for the production of certain types of proteins the brain needs for normal development. Mutations in these genes stop the production of these proteins, while causing other genes to function abnormally, resulting in atypical brain development and loss of abilities.
Since RS is tied to genes on the X chromosome, one of two chromosomes responsible for determining sex, it is classified as an X-linked genetic disorder. Autosomal genetic disorders, in contrast, have genetic abnormalities or mutations on non-sex related chromosomes. Therefore, the simple answer to the question is Rett Syndrome autosomal is no, since RS is directly linked to the mutation of genes on the X chromosome.
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Macrocephaly And Overgrowth Syndromes
The macrocephaly observed in approximately 15/100 to 35/100 of individuals with autism appears to be an independent clinical trait, not related to sex, the presence of morphological abnormalities, IQ, occurrence of seizures, or the severity of autistic symptoms. It is typically not present at birth but becomes manifest at around 1 to 3years of age., Although macrocephaly is one of the most widely replicated neurobiological findings in autism, its pathogenesis remains unknown. Converging evidence from head circumference measurements, magnetic resonance imaging studies, and postmortem brain weight indicates that a large proportion of children with autism have an abnormal regulation of brain growth, resulting in enlarged brains during early childhood. Other studies, however, have found increased brain volume in populations of older individuals with autism, so the timing of brain enlargement remains to be determined. Similarly, the pattern of enlargement across the brain lobes and cerebellum, and the involvement of grey versus white matter, is still unclear at present.
In addition, germline PTEN gene mutations have been reported in children with autism and macrocephaly, and autism with no other clinical features, and it has been suggested that PTEN gene sequencing be included in the diagnostic work-up of these children.
Brain Expression Patterns Of Rigs And Dngs
RNA-seq data from the BrainSpan database were used to determine the spatiotemporal expression patterns of ASD-associated RIGs and DNGs, as described in previous studies . Hybrid-weighted gene co-expression network analysis was conducted to cluster ASD-associated RIGs and DNGs into different co-expression modules using standard protocols and at a power of four. Additionally, we sourced transcriptome data from different layers of the developing neocortex and characterized the laminar expression patterns of ASD-associated RIGs and DNGs by using WGCNA at a power of three. Furthermore, we downloaded a single-cell RNA-seq dataset from 15,928 nuclei in the human middle temporal gyrus from the Allen Brain Map database . These transcriptional profiles showed the RNA levels of all genes in 45 types of inhibitory neurons and 24 types of excitatory neurons. For each gene in each nucleus, the RPKM value was calculated based on the counts per million value downloaded from the Allen Brain Map database. Subsequently, the average expression of each gene in each neuronal type was quantified. Differences in ASD gene expression in inhibitory and excitatory neurons were evaluated by the Wilcoxon-rank sum test.
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Sex Chromosome Clue To Autism
By Emily Singer
A small group of genes on the X chromosome regulate the brains threat-detector and might explain the high prevalence of autism among males, researchers have discovered.
Some people lacking these genes have problems recognising fear in another persons face, a common trait in autism. They also have abnormal amygdalas a brain area known as the fear centre.
The results provide a possible genetic mechanism for the sex bias of autism. Other recent research has identified a gene in the same region of the X chromosome that correlates with the severity of autism. However, confirmation of this explanation of autisms sex bias is still far off researchers have not yet determined which specific gene or genes are responsible and have not looked at the function of these genes in autistic people.
Previous research suggests autism has a genetic basis, but so far, no single gene has been located that causes the disease in the general population. Autism is 10 times more prevalent among boys than girls, suggesting that a genetic factor may be sex-linked.
The answer must lie in the sex chromosome, said David Skuse, from the Institute of Child Health in London, speaking at the British Association Festival of Science in Salford, near Manchester, UK, on Tuesday.
There Are Certainly Some Genetic Factors That Seem To Play Into Whether Someone Will Develop Autism But It Isn’t As Simple As Dominant/recessive Genes
A single abnormal gene on one of the first 22 nonsex chromosomes from either parent can cause an autosomal disorder. Looking at my family line, there really anyone else that has a class 3 underbite like me. This is an autosomal recessive peroxismal disorder resulting from homozygous mutations in receptor gene mutations such as pex1, pex5, pex13, and pex26. In autism, it depends on which parent passes on the genetic abnormality. Autosomal dominant vs recessive vs x linked klinefelter s syndrome dominant or recessive connect by text or video with a u.s. If the heritability of a condition is high, then the condition is considered to be primarily genetic. Environmental factors, diet, vaccines, and. Inheritance of traits like diseases depends on how many are inherited and whether they are dominant or recessive. However, little work has been done to indicate whether this issue with fmrp is inherited I was wondering what are the chances of my children receiving my underbite? The mri scan of the brain demonstrates hypomyelination. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. While it has been known that genetic abnormalities.
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Relatively Less Complex Genetic And Chromosomal Disorders
A few relatively less complex genetic or chromosomal disorders include prominent neuropsychiatric symptoms relevant to ASD. Since the etiology of these disorders is partially known, investigators can hope to gain insight into the more complex genetics of ASD by studying the molecular and brain system abnormalities both in humans with these diseases and in corresponding lower mammallian disease models. A number of other simple genetic diseases primarily affect other systems but also commonly share some features of autism spectrum disorder. For example, SmithLemliOpitz syndrome results from a defect in cholesterol synthesis and involves structural deficits throughout the body, but many SLOS patients also have ASD symptoms that may relate to abnormal serotonergic development. More single gene or chromosomal disorders will likely be identified from within the heterogeneous syndrome of ASD.
Maternal chromosome 15q1113 duplications and triplications are the most common relatively less complex genetic syndrome identified to date in samples of patients with autism spectrum disorders. This syndrome is discussed above as part of example II.
Functional Clusters Of Asd
Co-expression and PPI data were used to construct a functional network of RIGs and DNGs. We paired any two ASD-associated RIGs or DNGs if they were co-expressed or found to interact at the protein level and combined these relationships to form an interconnected network, which was visualized in Cytoscape . Gene ontology enrichment analysis of RIGs and DNGs was performed by using Metascape with default parameters. Similar GO terms were merged, and only the most significant GO term in each cluster was shown. Additionally, we sourced fragile X mental retardation protein targets and essential genes , as described in a previous study .
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Genetic Causes And Modifiers Of Autism Spectrum Disorder
- Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
Autism Spectrum Disorder is one of the most prevalent neurodevelopmental disorders, affecting an estimated 1 in 59 children. ASD is highly genetically heterogeneous and may be caused by both inheritable and de novo gene variations. In the past decade, hundreds of genes have been identified that contribute to the serious deficits in communication, social cognition, and behavior that patients often experience. However, these only account for 1020% of ASD cases, and patients with similar pathogenic variants may be diagnosed on very different levels of the spectrum. In this review, we will describe the genetic landscape of ASD and discuss how genetic modifiers such as copy number variation, single nucleotide polymorphisms, and epigenetic alterations likely play a key role in modulating the phenotypic spectrum of ASD patients. We also consider how genetic modifiers can alter convergent signaling pathways and lead to impaired neural circuitry formation. Lastly, we review sex-linked modifiers and clinical implications. Further understanding of these mechanisms is crucial for both comprehending ASD and for developing novel therapies.