Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

Yuan, Bo; Pehlivan, Davut; Karaca, Ender; Nisha, Patel; Charng, Wu Lin; Gambin, Tomasz; Gonzaga‐Jauregui, Claudia; Sutton, V. Reid; Yeşil, Gözde; Bozdoğan, Sevcan Tuğ; Tos, Tülay; Koparır, Asuman; Koparir, Erkan; Beck, Christine R.; Gu, Shen; Aslan, Hüseyin; Yüreğir, Özge Özalp; Rubeaan, Khalid Al; Alnaqeb, Dhekra; Alshammari, Muneera; Bayram, Yavuz; Atik, Mehmed M.; Aydın, Hatip; Geçkinli, Bilgen Bilge; Seven, Mehmet; Ulucan, Hakan; Fenercioğlu, Elif; Özen, Mustafa; Jhangiani, Shalini N.; Muzny, Donna M.; Boerwinkle, Eric; Tüysüz, Beyhan; Alkuraya, Fowzan S.; Gibbs, Richard A.; Lupski, James R.

doi:10.1172/jci77435

Cited by 139 publications

(159 citation statements)

References 57 publications

(58 reference statements)

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“…Altogether, these clinical similarities caused by different genes, coding for functionally related proteins, fully agree with the recently proposed concept of "transcriptomopathies", a class of disorders that may reflect a global disturbance in transcriptional regulation (40).…”

Section: Articlessupporting

confidence: 86%

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

et al. 2016

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Background: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. Methods: Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. results: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. conclusion: The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/ MED13L clinical spectrum, encompassing Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others.

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Section: Articlessupporting

confidence: 86%

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

et al. 2016

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“…The effect was particularly marked with the c.119T>A (p.Met40Lys) variant. In addition to these clinical, genetic, modeling, and biochemical results, the fact that mutations in other components of the TFIID complex (TAF1, TAF2, TAF6, and TBP) lead to a neurological phenotype [8][9][10][11][12][13][14][15] strongly supports our hypothesis that bi-allelic pathogenic alterations in the histone fold domain of TAF13 lead to mild ID and microcephaly. TAF13 is a constituent of at least two protein complexes: the TFIID complex and the small nuclear RNA genespecific TAF complex (snTAFc), which play a critical role in the regulation of gene transcription in eukaryotic cells.…”

supporting

confidence: 70%

Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

Tawamie

Martianov

Wohlfahrt

et al. 2017

The American Journal of Human Genetics

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In two independent consanguineous families each with two children affected by mild intellectual disability and microcephaly, we identified two homozygous missense variants (c.119T>A [p.Met40Lys] and c.92T>A [p.Leu31His]) in TATA-box-binding-protein-associated factor 13 (TAF13). Molecular modeling suggested a pathogenic effect of both variants through disruption of the interaction between TAF13 and TAF11. These two proteins form a histone-like heterodimer that is essential for their recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Co-immunoprecipitation in HeLa cells transfected with plasmids encoding TAF11 and TAF13 revealed that both variants indeed impaired formation of the TAF13-TAF11 heterodimer, thus confirming the protein modeling analysis. To further understand the functional role of TAF13, we performed RNA sequencing of neuroblastoma cell lines upon TAF13 knockdown. The transcriptional profile showed significant deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions and those containing E-box motives in their promoters. Here, we expand the spectrum of TAF-associated phenotypes and highlight the importance of TAF13 in neuronal functions.

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“…Exomes were captured and sequenced on an Illumina HiSeq platform using previously described methods [19]. Sequence analysis was performed using the HGSC Mercury analysis pipeline (https://www.hgsc.bcm.edu/software/mercury) [20].…”

Section: Methodsmentioning

confidence: 99%

“…Variants were filtered based on inheritance patterns including autosomal recessive, X-linked, and de novo/autosomal dominant. Variants with MAF < 0.05 in control cohorts (Atherosclerosis Risk in Communities (ARIC, https://www2.cscc.unc.edu/aric/), 1000 Genomes project (http://www.1000genomes.org/), the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), and our internal BCM control database of > 5000 exomes generated as a member of the Centers for Mendelian Genomics) [21] and predicted to be deleterious by SIFT10 and/or PolyPhen were prioritized [19]. Sanger sequencing confirmed putatively causative variants and their familial segregation.…”

Section: Methodsmentioning

confidence: 99%

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

et al. 2016

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BackgroundSmith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors.MethodsWe investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes.ResultsPotentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 –/– mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 –/– mouse model.ConclusionsThese holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0359-z) contains supplementary material, which is available to authorized users.

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Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

Cited by 139 publications

References 57 publications

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy?

Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

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