Recent ultra-rare inherited variants implicate new autism candidate risk genes

Wilfert, Amy B.; Turner, Tychele N.; Murali, Shwetha C.; Hsieh, PingHsun; Sulovari, Arvis; Wang, Tianyun; Coe, Bradley P.; Guo, Hui; Hoekzema, Kendra; Bakken, Trygve E.; Winterkorn, Lara; Evani, Uday S.; Byrska-Bishop, Marta; Earl, Rachel K.; Bernier, Raphael; Zhou, Xueya; Feliciano, Pamela; Hall, Jacob B.; Astrovskaya, Irina; Xu, Simon Xuming; Shu, Chang; Obiajulu, Joseph; Brueggeman, Leo; Wright, Jessica; Марченко, Олена Геннадіївна; Fleisch, Chris; Chang, T. S.; Snyder, LeeAnne Green; Barns, Sarah; Han, Bing; Harvey, William T.; Nishida, Andrew; Doan, Ryan; Soucy, Aubrey; O’Roak, Brian J.; Yu, Timothy W.; Geschwind, Daniel H.; Michaelson, Jacob; Volfovsky, Natalia; Shen, Yufeng; Chung, Wendy K.; Zody, Michael C.; Eichler, Evan E.

doi:10.1038/s41588-021-00899-8

Cited by 81 publications

(80 citation statements)

References 97 publications

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“…The association between de novo SNVs and ASD/ID has been demonstrated by different studies, firstly for disruptive variants [43]. Recently, an enrichment of multiple de novo variants in various genes found via large-scale exome sequencing has suggested the involvement of an oligogenic model in patients with ASD [44]. Our findings are in agreement with the theory of a multi-hit model in the pathogenesis of ASD and ID [45].…”

Section: Discussionsupporting

confidence: 89%

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

Bruno

Doddato

Valentino

et al. 2021

IJMS

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Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1–3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent–offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.

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Section: Discussionsupporting

confidence: 89%

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

Bruno

Doddato

Valentino

et al. 2021

IJMS

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“…Cohort #2 is the ITMI Childhood Longitudinal Cohort Study cohort ( Goldmann et al 2018 ). Cohort #3 is a combination of the SSC, TASC, and SAGE study cohorts sequenced at the New York Genome Center ( Wilfert et al 2021 ). Cohort #4 is a collection of large families from the Centre d'Etude du Polymorphisme Humain (CEPH) consortium ( Sasani et al 2019 ; Dausset et al 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Differences in the number of de novo mutations between individuals are due to small family-specific effects and stochasticity

et al. 2021

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The number of de novo mutations (DNMs) in the human germline is correlated with parental age at conception, but this explains only part of the observed variation. We investigated whether there is a family-specific contribution to the number of DNMs in offspring. The analysis of DNMs in 111 dizygotic twin pairs did not identify a substantial family-specific contribution. This result was corroborated by comparing DNMs of 1669 siblings to those of age-matched unrelated offspring following correction for parental age. In addition, by modeling DNM data from 1714 multi-offspring families, we estimated that the family-specific contribution explains ∼5.2% of the variation in DNM number. Furthermore, we found no substantial difference between the observed number of DNMs and those predicted by a stochastic Poisson process. We conclude that there is a small family-specific contribution to DNM number and that stochasticity explains a large proportion of variation in DNM counts.

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“…The variants were annotated using snpEff [23] v4.3 and Annovar [24] v20191024. We focused on URVs as these have shown a strong burden of deleterious pathogenic variants in multiple studies of epilepsy and other neurological disorders [ 8 , 10 , 11 , [25] , [26] , [27] , [28] , [29] ]. URVs were defined based on their Minor Allele Counts (MACs) in the study dataset (internal allele count/frequency) and their estimated frequency in the general population (external Minor Allele Frequencies, MAFs).…”

Section: Methodsmentioning

confidence: 99%

Distinct gene-set burden patterns underlie common generalized and focal epilepsies

et al. 2021

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Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. Methods The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. Findings Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. Interpretation Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. Funding DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).

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Recent ultra-rare inherited variants implicate new autism candidate risk genes

Cited by 81 publications

References 97 publications

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

Differences in the number of de novo mutations between individuals are due to small family-specific effects and stochasticity

Distinct gene-set burden patterns underlie common generalized and focal epilepsies

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