An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio

Sadybekov, Anastasiia; Tian, Chen; Arnesano, Cosimo; Katritch, Vsevolod; Herring, Bruce E.

doi:10.1038/s41467-017-00472-0

Cited by 107 publications

(149 citation statements)

References 56 publications

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“…In contrast to other GEF1 domain variants involved in ASD, the p.Asp1368Val has been demonstrated to results in TRIO hyperfunction (Sadybekov et al, 2017). This finding may explain the more severe phenotype associated to the p.Asp1368Val, and those of the proband we report, carrying the p.His1371Tyr, presenting with severe ID, epilepsy, absent speech, and macrocephaly.…”

Section: Discussioncontrasting

confidence: 53%

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Aspromonte

Bellini

Gasparini

et al. 2019

Preprint

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Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next generation sequencing (NGS) gene panel that has been transferred into clinical practice, replacing single disease gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%.Our data also support the pathogenic role of genes recently proposed to be involved in ASD.Although many of the identified variants need further investigation to be considered diseasecausing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

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Section: Discussioncontrasting

confidence: 53%

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Aspromonte

Bellini

Gasparini

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…These variants may perturbe specific subset of links in the interactome. For instance, different mutations in ARX gene, a paradigm of a pleiotropic gene, have been associated with diverse defects involving GABAergic neurons and associated with a wide spectrum of disorders (Friocourt & Parnavelas, 2010 In contrast to other GEF1 domain variants involved in ASD, the p.Asp1368Val has been demonstrated to results in TRIO hyperfunction (Sadybekov, Tian, Arnesano, Katritch, & Herring, 2017). This finding may explain the more severe phenotype associated with the p.Asp1368Val, and those of the proband we report, carrying the p.His1371Tyr, presenting with severe ID, epilepsy, absent speech, and macrocephaly.…”

Section: Discussionmentioning

confidence: 99%

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

et al. 2019

View full text Add to dashboard Cite

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low‐cost next‐generation sequencing gene panel that has been transferred into clinical practice, replacing single disease‐gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease‐gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease‐causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

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“…The number of such mutations is small (12 in probands, 7 in siblings), but includes multiple genes previously implicated to be involved in ASD or related neurodevelopmental disorders ( e.g. , DIP2B 42 , POLG 43 , ADRA2A 44 , TRIOBP 45 , HDAC2 46 , HECTD2 47 have mutations resulting in previously unobserved TR alleles in probands; Supplementary Fig. 14 ).…”

Section: Tr Mutation Burden In Asdmentioning

confidence: 99%

Genome-wide patterns ofde novotandem repeat mutations and their contribution to autism spectrum disorders

Mitra

Huang

Mousavi

et al. 2020

Preprint

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Recent studies have demonstrated a strong contribution of germline de novo mutations to autism spectrum disorders (ASD). Tandem repeats (TRs), consisting of repeated sequence motifs of 1-20bp, comprise one of the largest sources of human genetic variation. Yet, the contribution of TR mutations to ASD has not been assessed on a genome-wide scale. Here, we leverage novel bioinformatics tools and~35 × whole genome sequencing of~1,600 families from the Simons Simplex Collection (SSC) to analyze germline de novo TR mutations at nearly 1 million loci in ASD-affected and unaffected siblings. We identify an average of 54 high-confidence mutations per child at an estimated true positive rate of 90%. We find novel genome-wide TR mutation patterns, including a bias toward larger mutations from the maternal compared with paternal germlines. We demonstrate a significant genome-wide excess of TR mutations in ASD probands, which are significantly larger than in controls, enriched in promoters of fetal brain expressed genes, and more strongly predicted to alter expression during brain development. Overall, our results indicate a significant, but so far overlooked, contribution of repetitive regions to ASD.

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An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio

Cited by 107 publications

References 56 publications

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Characterization of Intellectual disability and Autism comorbidity through gene panel sequencing

Characterization of intellectual disability and autism comorbidity through gene panel sequencing

Genome-wide patterns ofde novotandem repeat mutations and their contribution to autism spectrum disorders

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