Excess of rare, inherited truncating mutations in autism

Krumm, Niklas; Turner, Tychele N.; Baker, Carl; Vives, Laura; Mohajeri, Kiana; Witherspoon, Kali; Raja, Archana; Coe, Bradley P.; Stessman, Holly A.F.; He, Zong Xiao; Leal, Suzanne M.; Bernier, Raphael; Eichler, Evan E.

doi:10.1038/ng.3303

Cited by 538 publications

(607 citation statements)

References 53 publications

(92 reference statements)

Supporting

Mentioning

575

Contrasting

Unclassified

Order By: Relevance

“…That autism candidate genes have a reduced load of damaging mutation has been reported earlier by others using different methods for measuring tolerance of mutation based largely on missense mutation and/or overlapping autism sample sets (13,14,16). Our results strengthen this finding with somewhat stronger statistics by using a larger set of target genes divided by severity, by using a larger control population to hone the tolerance score, or both.…”

Section: Discussionsupporting

confidence: 80%

See 1 more Smart Citation

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.

141

144

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 80%

“…They apply their particular tolerance score on targets from a subset of the Simons Simplex Collection (SSC), a collection of simplex autism families (5,7,8,15). More recently, additional evidence has been shown for transmission of mutations in genes with low tolerance using the RVIS from mothers (16).…”

mentioning

confidence: 99%

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.

141

144

View full text Add to dashboard Cite

show abstract

“…Based on current estimates, one-fifth of these uncharacterized genes (∼2,000) are expected to be EGs, which may explain the higher mutational burden of dnLoF variants in ASD probands. Recent studies have begun to show that additional genetic factors, such as rare and common inherited variations, also contribute to ASD (26,46). Our result supports this finding, showing that inherited, rare, damaging mutations in EGs also have a significant effect on ASD risk.…”

Section: B C Asupporting

confidence: 81%

“…To address a possible cumulative effect of variants in EGs in ASD in a larger cohort of 1,781 ASD quartet families (with 1,781 probands and 1,781 siblings) from the Simons Simplex Collection (34), we acquired de novo and rare inherited mutations from the exome sequencing data of these families (8,26). We examined the individual mutational burden defined by the number of de novo loss-of-function (dnLoF), de novo nonsynonymous damaging (dnNSD), and inherited rare damaging (inhRD) mutations per individual (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Several groups reported an enrichment of de novo and rare inherited single-nucleotide loss-of-function variants in ASD probands (8,26), although there is a depletion of damaging mutations in ASD risk genes in population controls (12,27,28). In this report, we compiled, to our knowledge, the most comprehensive list of human EGs and extended the analysis to both de novo and inherited damaging variants in 1,781 ASD families.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Xiao

Kember

Brown

et al. 2016

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

View full text Add to dashboard Cite

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre-and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.essential genes | mouse knockouts | mutational burden | autism spectrum disorder | coexpression modules A utism spectrum disorder (ASD) is a heterogeneous, heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior (1, 2). The highly polygenic nature of ASD (3-5) suggests that the analysis of the full spectrum of sequence variants in hundreds of genes will be necessary for deeper understanding of disrupted neuronal function. Prioritization of ASD risk genes initially focused on known pathways with recognized relevance to pathogenesis of ASD, such as synaptic function and neuronal development (6). However, combined analyses of de novo, inherited, and case-control variation in over 2,500 ASD parentchild nuclear families identified around 100 genes contributing to ASD risk (7-9), converging on pathways implicated in transcriptional regulation and chromatin modeling in addition to synaptic function.The main challenge in the current understanding of genetic architecture of ASD comes from a need to study the interplay between variants with a high effect (for example, recurrent de novo variants) and a background of variants with an intermediate effect but that nevertheless still disrupt proper neuronal development. Essential genes (EGs) or genes that are necessary for successful completion of pre-and postnatal development are prime candi...

show abstract

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye

Li¹,

Wang²,

Lee³

et al. 2021

JAMA

View full text Add to dashboard Cite

The Genetics of Exfoliation Syndrome Partnership IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTSA 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURESThe primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10 −6 . The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTSThe discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10 −7 ). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < ....

show abstract

Excess of rare, inherited truncating mutations in autism

Cited by 538 publications

References 53 publications

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

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

Increased burden of deleterious variants in essential genes in autism spectrum disorder

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye

Contact Info

Product

Resources

About