The Familial Risk of Autism

Sandin, Sven; Lichtenstein, Paul; Kuja‐Halkola, Ralf; Larsson, Henrik; Hultman, Christina M.; Reichenberg, Abraham

doi:10.1001/jama.2014.4144

Cited by 933 publications

(738 citation statements)

References 34 publications

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“…Previous theory also predicted a preferred role for the mother in transmission, based largely on the reduced incidence of autism in females. Earlier population studies have indicated the importance of a shared maternal bloodline in sibling risk (19,20). In support of these reports, we find that the majority of the signal of biased transmission of UR LGD variants in vulnerable genes comes from the maternal line.…”

Section: Discussionsupporting

confidence: 88%

Low load for disruptive mutations in autism genes and their biased transmission

Iossifov

Levy

Allen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

150

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We previously computed that genes with de novo (DN) likely gene-disruptive (LGD) mutations in children with autism spectrum disorders (ASD) have high vulnerability: disruptive mutations in many of these genes, the vulnerable autism genes, will have a high likelihood of resulting in ASD. Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure. An immediate prediction is that these genes will have a lower LGD load than typical genes in the human gene pool. We confirm this hypothesis in an explicit test by measuring the load of disruptive mutations in wholeexome sequence databases from two cohorts. We use information about mutational load to show that lower and higher intelligence quotients (IQ) affected individuals can be distinguished by the mutational load in their respective gene targets, as well as to help prioritize gene targets by their likelihood of being autism genes. Moreover, we demonstrate that transmission of rare disruptions in genes with a lower LGD load occurs more often to affected offspring; we show transmission originates most often from the mother, and transmission of such variants is seen more often in offspring with lower IQ. A surprising proportion of transmission of these rare events comes from genes expressed in the embryonic brain that show sharply reduced expression shortly after birth.autism spectrum disorder | gene vulnerability | disruptive mutations | biased transmission | autism genes T he past decade has seen remarkable progress in understanding genetic causation of autism spectrum disorders (ASD), confirmatory of predictions made by a "unified" genetic theory of autism proposed in 2007 (1). This theory proposes that much of ASD is caused by new mutation, sometimes directly contributing to the disorder through germ-line mutation, or transmitted by parents, especially females, who carry a variant of recent vintage without experiencing severe consequences. The theory was based largely on three sets of observations: (i) low ASD incidence in females compared with males (2), (ii) apparently dominant transmission to male children in multiplex families (1), and (iii) greater incidence of de novo (DN) copy number mutation in children with ASD than in their siblings in simplex families (3, 4). Since then, evidence for causal DN mutation has accumulated (5-8). These damaging mutations generally affect only one allele, suggesting that gene targets are dosage-sensitive, prone to dominant negative mutation, or some combination of these factors.A widely held genetic model for autism is that combinations of common variation are the major driving force. As we argue, there is little evidence for this belief. Damaging DN mutation contributes to at least 30% of ASD in simplex families (9). Among such damaging mutations are those mutations that are likely gene-disruptive (LGD) in that they create nonsense, splice-site, or small frame-shift variants (5). The estimates of contribution from DN mutations derive from the statistical...

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Section: Discussionsupporting

confidence: 88%

Low load for disruptive mutations in autism genes and their biased transmission

Iossifov

Levy

Allen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

146

150

View full text Add to dashboard Cite

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“…Despite the high prevalence of ASD (recent reports indicate that as many as 1 in 68 children are born with ASD), a specific etiology is identified in <20 % of patients (as reviewed in [26]). Notwithstanding, there is a significant genetic component to ASD, as illustrated by the observation that 1) risk of recurrence is approximately 20 % for siblings, and 2) concordance for autism in monozygotic twins is 8 times higher than in dizygotic twins [27][28][29][30][31]. For this reason, considerable effort has been invested into identifying human genetic causes of ASD.…”

Section: As and Autismmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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“…It is multifactorial in background with high heritability (Sandin et al 2014) and the underlying neurobiological mechanisms have yet to be determined. Current research is looking at gene-environment interaction models to explain the etiology and also the variations in phenotypic expression (Chaste and Leboyer 2012).…”

Section: Discussionmentioning

confidence: 99%