Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

Sluijs, Pleuntje J. van der; Joosten, Marieke; Alby, Caroline; Attié‐Bitach, Tania; Gilmore, Kelly; Dubourg, Christèle; Fradin, Mélanie; Wang, Tianyun; Kurtz-Nelson, Evangeline; Ahlers, Kaitlyn; Arts, Peer; Barnett, Christopher; Ashfaq, Myla; Baban, Anwar; Born, Myrthe van den; Borrie, Sarah; Busa, Tiffany; Byrne, Alicia B.; Carriero, Miriam Lucia; Cesario, Claudia; Cueto‐González, Anna M.; Dempsey, Jennifer C.; Diderich, Karin E. M.; Doherty, Dan; Farholt, Stense; Gerkes, Erica H.; Gorokhova, Svetlana; Govaerts, L.; Gregersen, Pernille A; Hickey, Scott E.; Lefebvre, Mathilde; Mari, Francesca; Martinovic, Jéléna; O’Leary, Melanie; Parbhoo, Kareesma; Patrier, Sophie; Popp, Bernt; Santos‐Simarro, Fernando; Stoltenburg, Corinna; Thauvin‐Robinet, Christel; Thompson, Elisabeth Morgan; Silfhout, Anneke T. Vulto-van; Zahir, Farah; Scott, Hamish S.; Earl, Rachel K.; Eichler, Evan E.; Vora, Neeta L.; Wilnai, Yael; Giordano, Jessica L.; Wapner, Ronald J.; Rosenfeld, Jill A.; Haak, Monique; Santen, Gijs W.E.

doi:10.1016/j.gim.2022.04.010

Cited by 10 publications

(19 citation statements)

References 25 publications

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“…A subsequent ARID1A - wildtype iPSC line was used as a control (CTRL1). While full mutations in ARID1A lead to a severe CSS subtype with multiple congenital anomalies and reduced survival, mosaic variants are often observed in individuals with a more moderate CSS phenotype 42 . The ARID1A -haploinsufficient patient fibroblasts (PT1 and PT2) were reprogrammed into iPSCs (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial to mesenchymal transition in cranial neural crest lineage commitment

Barnada,

de Gracia,

Morenilla-Palao

et al. 2024

Preprint

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The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris Syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of CSS patients carry variants in one of the mutually exclusive BAF subunits,ARID1A/ARID1B. WhileArid1adeletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS patient-derivedARID1A+/-iPSCs to model CNCC specification, we discoveredARID1A-haploinsufficiency impairs epithelial to mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion ofZic2impairs NCC delamination, whileZIC2overexpression in chick embryos at pre-migratory neural crest stages elicits ectopic delamination from the neural tube. These findings reveal a novel ARID1A-ZIC2 axis essential for EMT and CNCC delamination.

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Section: Resultsmentioning

confidence: 99%

ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial to mesenchymal transition in cranial neural crest lineage commitment

Barnada,

de Gracia,

Morenilla-Palao

et al. 2024

Preprint

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“…11 The research group also reported hypoplastic left heart syndrome in 1 fetus with ARID1B and 2 fetuses with SMARCA4 pathogenic variants. 11 Also a case with prenatal CSS related to SMARCC2 with tetralogy of Fallot has been reported. 14 The analysis of clinically significant genes of fetus 1 showed a frameshift causing variant in SMARCB1 as the cause for CSS3 and a small deletion in ARID1A as the cause of CSS2 in fetus 2.…”

Section: Discussionmentioning

confidence: 95%

“…A recently reported fetal cohort with SMARCB1 pathogenic variants did not show more severe cardiac manifestations compared to other pathogenic variants and the fetuses with ARID1A pathogenic variants were more likely to perish in the neonatal period than the non-ARID1A fetuses. 11 Both fetuses had typical dysmorphic features including hypertelorism and micrognathia as well as corpus callosum agenesis. The CNS malformations have been reported frequently in CSS.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease

Keskinen,

Paakkola,

Mattila

et al. 2023

Pediatr Dev Pathol

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Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.

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“…Although rare, prenatal manifestations of CSS have also been reported. 3,4 As most variants are de novo, it would be important to know the fetal sonographic markers of CSS in order to inform its prenatal diagnosis. In this study, we describe prenatal features detected by ultrasound in eight fetuses with CSS, all of which were diagnosed by the detection of pathogenic variants in genes of the BAF complex.…”

Section: Introductionmentioning

confidence: 99%

Prenatal diagnosis of Coffin‐Siris syndrome: What are the fetal features?

Jing

Lin

et al. 2022

Prenatal Diagnosis

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Objective: To present both our center's and previously reported experience of prenatal diagnosis of Coffin-Siris syndrome (CSS) with regard to the laboratory testing and fetal features of this syndrome. Methods:This was a retrospective study of eight pregnancies with fetal CSS identified by prenatal or postnatal genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray and exome sequencing (ES) results, and pregnancy outcomes.Results: A total of eight cases of fetal CSS based on molecular testing were detected. Two cases presented with an increased nuchal translucency (NT) in the first trimester. The remaining six were identified at the second trimester scan.Agenesis of the corpus callosum (ACC) was the most common sonographic finding, accounting for 5/7 (71.4%) cases in which a second trimester sonogram was performed: four had ACC as an isolated finding, and one had additional features of cerebellar hypoplasia and left congenital diaphragmatic hernia. Conclusion:CSS should be included in the differential diagnosis when ACC is found by prenatal ultrasound. Both chromosomal microarray and ES should be options when counseling patients with a structurally anomalous fetus. Key points What is already known on this topic?� Coffin-Siris syndrome (CSS) is inherited in an autosomal dominant manner; most affected individuals have the disorder as the result of de novo CSS-causing variants of genes in the BAF complex.� In postnatal patients, the diagnosis is based on the presence of major and at least one minor clinical sign. What this study adds?� CSS should be included in the differential diagnosis when a fetus presents with agenesis of the corpus callosum.� In addition to chromosomal microarray, exome sequencing should be an option when counseling patients with a structurally anomalous fetus.Qiu-Xia Yu and Xiang-Yi Jing contributed equally to this study.

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Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

Cited by 10 publications

References 25 publications

ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial to mesenchymal transition in cranial neural crest lineage commitment

ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial to mesenchymal transition in cranial neural crest lineage commitment

Prenatal Coffin-Siris Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Disease

Prenatal diagnosis of Coffin‐Siris syndrome: What are the fetal features?

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