Phenotype associated with TAF2 biallelic mutations: A clinical description of four individuals and review of the literature

Lesieur-Sebellin, Marion; Capri, Yline; Grisval, Margot; Courtin, Thomas; Burtz, Augustine; Thévenon, Julien; Buratti, Julien; Lejeune, Élodie; Faivre, Laurence; Keren, Boris

doi:10.1016/j.ejmg.2021.104323

Cited by 8 publications

(6 citation statements)

References 9 publications

(10 reference statements)

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“…Pathogenic TAF2 variants cause moderate/severe NDD and a thin or absent corpus callosum (OMIM: 614340). The TAF2 variant was a possible candidate although it was not fully explanatory for the full agenesis of the corpus callosum and the pons abnormality of individual 9 (62, 63). Furthermore, we still observed normal splicing in 65% of the reads and we were puzzled by the fact that TAF2 tolerates heterozygous loss-of-function variants (pLI = 0; gnomAD v.2.1.1).…”

Section: Resultsmentioning

confidence: 98%

RNA-sequencing improves diagnosis for neurodevelopmental disorders by identifying pathogenic non-coding variants and reinterpretation of coding variants

Dekker

Schot

Bongaerts

et al. 2022

Preprint

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BackgroundFor neurodevelopmental disorders (NDD), a molecular diagnosis is key for predicting outcome, treatment and genetic counseling. Currently, in about half of NDD cases, routine DNA-based testing fails to establish a genetic diagnosis. Transcriptome analysis (RNA-seq) improves the diagnostic yield for some groups of diseases, but has not been applied to NDD in a routine diagnostic setting.MethodsHere, we explored the diagnostic potential of RNA-seq in a cohort of 96 individuals including 67 undiagnosed NDD subjects. We created a user-friendly web-application to analyze RNA-seq data from single individuals’ cultured skin fibroblasts for genic, exonic and intronic expression outliers, based on modified OUTRIDER Z-scores. Candidate pathogenic events were complemented/matched with genomic data and, if required, confirmed with additional functional assays.ResultsWe identified pathogenic small genomic deletions, mono-allelic expression, aberrant splicing events, deep intronic variants resulting in pseudo-exon insertion, but also synonymous and nonsynonymous variants with deleterious effects on transcription. This approach increased the diagnostic yield for NDD by 12%. Diagnostic pitfalls during transcriptome analysis include detection of splice abnormalities in putative disease genes caused by benign polymorphisms and/or absence of expression of the responsible gene in the tissue of choice. This was misleading in one case and could have led to the wrong diagnosis in the absence of appropriate phenotyping.ConclusionsNonetheless, our results demonstrate the utility of RNA-seq in molecular diagnostics and stress the importance of multidisciplinary team consultation. In particular, the approach is useful for the identification and interpretation of unexpected pathogenic changes in mRNA processing and expression in NDD.

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Section: Resultsmentioning

confidence: 98%

RNA-sequencing improves diagnosis for neurodevelopmental disorders by identifying pathogenic non-coding variants and reinterpretation of coding variants

Dekker

Schot

Bongaerts

et al. 2022

Preprint

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“…43 TAF2 acts as a stabilizer in binding TFIID to the core promoter. 44 TAF6 encodes part of the core of the TFIID complex, and defective TAF6 can alter the assembly of TFIID. 45 Vacuolar Protein Sorting 13 Homolog B; VPS13B…”

Section: Category Function Of the Genes And Implicated Phenotypesmentioning

confidence: 99%

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort

Zare Ashrafi,

Akhtarkhavari,

Fattahi

et al. 2023

Arch Iran Med

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Background: Intellectual disability (ID) is a genetically heterogeneous condition, and so far, 1679 human genes have been identified for this phenotype. Countries with a high rate of parental consanguinity, such as Iran, provide an excellent opportunity to identify the remaining novel ID genes, especially those with an autosomal recessive (AR) mode of inheritance. This study aimed to investigate the most prevalent ID genes identified via next-generation sequencing (NGS) in a large ID cohort at the Genetics Research Center (GRC) of the University of Social Welfare and Rehabilitation Sciences. Methods: First, we surveyed the epidemiological data of 619 of 1295 families in our ID cohort, who referred to the Genetics Research Center from all over the country between 2004 and 2021 for genetic investigation via the NGS pipeline. We then compared our data with those of several prominent studies conducted in consanguineous countries. Data analysis, including cohort data extraction, categorization, and comparison, was performed using the R program version 4.1.2. Results: We categorized the most common ID genes that were mutated in more than two families into 17 categories. The most common syndromic ID in our cohort was AP4 deficiency syndrome, and the most common non-syndromic autosomal recessive intellectual disability (ARID) gene was ASPM. We identified two unrelated families for the 36 ID genes. We found 14 genes in common between our cohort and the Arab and Pakistani groups, of which three genes (AP4M1, AP4S1, and ADGRG1) were repeated more than once. Conclusion: To date, there has been no comprehensive targeted NGS platform for the detection of ID genes in our country. Due to the large sample size of our study, our data may provide the initial step toward designing an indigenously targeted NGS platform for the diagnosis of ID, especially common ARID in our population.

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“…Both mutations caused a reduction in interaction of TAF6 with other TFIID subunits ( Yuan et al, 2015 ). A total of ten patients have been identified with four genotypic TAF2 variants, in all cases comprising homozygous missense mutations ( Najmabadi et al, 2011 ; Halevy et al, 2012 ; Hellman-Aharony et al, 2013 ; Thevenon et al, 2016 ; Lesieur-Sebellin et al, 2021 ). Patients present with global developmental delay, moderate to severe ID, microcephaly and abnormalities in the corpus callosum (reviewed by Lesieur-Sebellin et al, 2021 ).…”

Section: Tfiidmentioning

confidence: 99%

“…A total of ten patients have been identified with four genotypic TAF2 variants, in all cases comprising homozygous missense mutations ( Najmabadi et al, 2011 ; Halevy et al, 2012 ; Hellman-Aharony et al, 2013 ; Thevenon et al, 2016 ; Lesieur-Sebellin et al, 2021 ). Patients present with global developmental delay, moderate to severe ID, microcephaly and abnormalities in the corpus callosum (reviewed by Lesieur-Sebellin et al, 2021 ). Furthermore, a single study has identified four patients with TAF13 mutations from two unrelated families ( Tawamie et al, 2017 ).…”

Section: Tfiidmentioning

confidence: 99%

Transcription Pause and Escape in Neurodevelopmental Disorders

2022

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Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

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Phenotype associated with TAF2 biallelic mutations: A clinical description of four individuals and review of the literature

Cited by 8 publications

References 9 publications

RNA-sequencing improves diagnosis for neurodevelopmental disorders by identifying pathogenic non-coding variants and reinterpretation of coding variants

RNA-sequencing improves diagnosis for neurodevelopmental disorders by identifying pathogenic non-coding variants and reinterpretation of coding variants

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort

Transcription Pause and Escape in Neurodevelopmental Disorders

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