<i>STAG1</i>mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability

Lehalle, Daphné; Mosca-Boidron, Anne-Laure; Begtrup, Amber; Boute-Benejean, Odile; Charles, Perrine; Cho, Megan T.; Clarkson, Amanda; Devinsky, Orrin; Duffourd, Yannis; Duplomb, Laurence; Gérard, Bénédicte; Jacquette, Aurélia; Kuentz, Paul; Masurel‐Paulet, Alice; McDougall, Carey; Moutton, Sébastien; Olivié, Hilde; Park, Soo‐Mi; Rauch, Anita; Revençu, Nicole; Rivière, Jean‐Baptiste; Rubin, Karol; Simonic, Ingrid; Shears, Deborah; Smol, Thomas; Tavares, Ana Lisa Taylor; Terhal, Paulien A; Thévenon, Julien; Gassen, Koen van; Vincent‐Delorme, Catherine; Willemsen, Marjolein H.; Wilson, Golder N.; Zackai, Elaine H.; Zweier, Christiane; Callier, Patrick; Thauvin‐Robinet, Christel; Faivre, Laurence

doi:10.1136/jmedgenet-2016-104468

Cited by 41 publications

(40 citation statements)

References 38 publications

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“…In the second category, we identified several interesting candidate genes including a de novo deletion including STAG1 and a de novo intragenic duplication in FGF12 . In both genes, only recently have pathogenic SNVs been reported in patients with neurodevelopmental disorders including epilepsy . We further identified a deletion including SETBP1 associated with Shinzel‐Gieidon syndrome and ID (OMIM 611060) and a duplication including HCN2, a gene in which SNVs exerting a gain‐of‐function effect have recently been suggested as a risk factor for genetic generalized epilepsies .…”

Section: Resultsmentioning

confidence: 91%

“…The patient in this study only showed severe epilepsy and ID, suggesting that the SETBP1 ‐mutation phenotype may be broader than previously described. One patient had a microdeletion, classified here as possibly pathogenic, which includes STAG1 , now linked with epilepsy as a cohesinopathy, and one patient carried a de novo intragenic duplication in FGF12 in which SNVs have recently been reported in patients with epileptic encephalopathies …”

Section: Discussionmentioning

confidence: 99%

“…In both genes, only recently have pathogenic SNVs been reported in patients with neurodevelopmental disorders including epilepsy. 24,25 We further identified a deletion including SETBP1 associated with Shinzel-Gieidon syndrome and ID (OMIM 611060) and a duplication including HCN2, a gene in which SNVs exerting a gain-of-function effect have recently been suggested as a risk factor for genetic generalized epilepsies. 26 HCN2 has also previously been associated with febrile epilepsy syndromes; interestingly, the patient carrying this CNV also had a history of febrile seizures.…”

Section: Possibly Pathogenic Cnvsmentioning

confidence: 99%

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Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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Summary Objective Copy number variations ( CNV s) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNV s to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV . We identified CNV s covering recently reported ( HNRNPU ) or emerging ( RORB ) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNV s, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNV s (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10 −9 ). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNV s. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNV s in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNV s. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Possibly Pathogenic Cnvsmentioning

confidence: 99%

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Diagnostic implications of genetic copy number variation in epilepsy plus

et al. 2019

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“…The convergent molecular pathogenesis of CHOPS and CdLS is evidenced by a similar pattern of dysregulated genes . Combined microarray and gene panel/WES/WGS disclosed the Xq25 microduplication syndrome where a copy number gain of STAG2 alone is responsible for the phenotype and the syndromic unspecific ID due to STAG1 mutation or microdeletion …”

Section: Dd/id Syndromes Caused By Defects In Chromatin Architecturalmentioning

confidence: 99%

Developmental disorders with intellectual disability driven by chromatin dysregulation: Clinical overlaps and molecular mechanisms

Larizza

Finelli

2018

Clinical Genetics

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Advances in genomic analyses based on next-generation sequencing and integrated omics approaches, have accelerated in an unprecedented way the discovery of causative genes of developmental delay (DD) and intellectual disability (ID) disorders. Chromatin dysregulation has been recognized as common pathomechanism of mendelian DD/ID syndromes due to mutation in genes encoding chromatin regulators referred as transcriptomopathies or epigenetic disorders. Common to these syndromes are the wide phenotypic breadth and the recognition of groups of distinct syndromes with shared signs besides cognitive impairment, likely mirroring common molecular mechanisms. Disruption of chromatin-associated transcription machinery accounts for the phenotypic overlap of Cornelia de Lange with KBG and with syndromes of the epigenetic machinery. The genes responsible for Smith-Magenis-related disorders act in interconnected networks and the molecular signature of histone acetylation disorders joins Rubinstein-Taybi-related syndromes. Deciphering pathway interconnection of clinically similar ID syndromes may enhance search of common targets useful for developing new therapeutics.

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“…Amongst all cohesin subunits and cofactors, SA2 is the one most frequently mutated in different cancer types, such as urothelial bladder carcinoma (26% of tumor samples) (Balbas-Martinez et al 2013;Solomon et al 2013), Ewing sarcoma (15-22% of tumor samples) (Brohl et al 2014;Tirode et al 2014) and or acute myeloid leukemia (6% of tumor samples) (Rocquain et al 2010). Interestingly, congenital loss-of-function mutations in SA1 and SA2 do not cause Cornelia de Lange syndrome (CdLS), the major syndrome linked to mutations in core cohesin components and co-regulators, but rather associate with developmental delay and various malformations (Lehalle et al 2017;Mullegama et al 2017;Soardi et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control

Casa¹,

Gines²,

Gusmao

et al. 2019

Preprint

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Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A and RAD21, cohesin contains in somatic cells one of two orthologous STAG subunits, SA1 or SA2. How these variable subunits affect the function of the cohesin complex is still unclear. SA1-and SA2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of SA1 and SA2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either SA1 or SA2. Following rapid depletion of either subunit, we perform high resolution Hi-C, RNA-sequencing and sequential ChIP studies to show that SA1 and SA2 do not co-occupy individual binding sites and have distinct ways how they affect looping and gene expression. These findings are supported at the single cell level by single-molecule localizations via dSTORM super-resolution imaging. Since somatic and congenital mutations of the SA subunits are associated with cancer (SA2) and intellectual disability syndromes with congenital abnormalities (SA1 and SA2), we verified SA1-/SA2-dependencies using human neural stem cells, hence highlighting their importance for understanding particular disease contexts.

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STAG1mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability

Cited by 41 publications

References 38 publications

Diagnostic implications of genetic copy number variation in epilepsy plus

Diagnostic implications of genetic copy number variation in epilepsy plus

Developmental disorders with intellectual disability driven by chromatin dysregulation: Clinical overlaps and molecular mechanisms

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control

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