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Purpose
Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS...
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... may fit with our previous finding that ARID1A variants in postnatal cases are frequently present in a mosaic state, 1 which suggests that nonmosaic pathogenic ARID1A variants may lead to an embryonically severe or lethal phenotype. The likely explanation for the relative lack of postnatal ARID1A variants (Table 2) is that most fetuses with full pathogenic variants display severe congenital anomalies, leading to a large proportion of pregnancy terminations as well as fetal and neonatal demise. Thus far, such cases were less likely to undergo extensive diagnostic sequencing. ...Citations
... Recently, more phenotypes in the cardiovascular system have been noticed in CSS patients [139]. Among fetuses, 67% of patients present cardiac anomalies, and 53% of patients present vascular anomalies [140]. For instance, one case study has reported that one fetus with SMARCC2 deficiency was diagnosed with tetralogy of Fallot, a rare congenital disease caused by a combination of four heart defects [141]. ...
Mature vascular smooth muscle cells (VSMC) exhibit a remarkable degree of plasticity, a characteristic that has intrigued cardiovascular researchers for decades. Recently, it has become increasingly evident that the chromatin remodeler SWItch/Sucrose Non-Fermentable (SWI/SNF) complex plays a pivotal role in orchestrating chromatin conformation, which is critical for gene regulation. In this review, we provide a summary of research related to the involvement of the SWI/SNF complexes in VSMC and cardiovascular diseases (CVD), integrating these discoveries into the current landscape of epigenetic and transcriptional regulation in VSMC. These novel discoveries shed light on our understanding of VSMC biology and pave the way for developing innovative therapeutic strategies in CVD treatment.
... Five were truncating (3 frameshift, 1 gene deletion and 1 intergenic microdeletion) and 1 was a missense. For the remaining 6 individuals, the coordinates of the variants were not availabe because the authors reported separetely the variation and the phenotype [15]. In our cohort of 12 individuals, the types of ARMs were anal atresia (5/12), anteriorly placed anus (5/12), imperforate anus (2/12). ...
... In this study, we discuss the phenotype-genotype correlation between anorectal malformations (ARMs) and Coffin-Siris syndrome (CSS). There have been more than 300 molecularly confirmed cases of Coffin-Siris syndrome reported in the literature [12,13,15].If we estimate at 500 the number of CSS in the literature, our cohort of 12 cases with ARMs would indicate a 1/40 prevalence of ARMs in CSS patients, which is 125 times higher than the 1/5000 estimated prevalence of ARMs in the general population. Of course, these calculations are only rough estimates, since we know neither the exact number of published CSS cases nor the number of cases in which clinical signs of ARMs have been sought and reported, and nor the exact prevalence of ARMs in the general population. ...
Anorectal malformations (ARMs) represent a wide spectrum of congenital anomalies of the anus and rectum, of which more than half are syndromic. Their etiology is highly heterogeneous and still poorly understood. We report a 4-year-old girl who initially presented with an isolated ARM, and subsequently developed a global developmental delay as part of an ARID1B-related Coffin-Siris syndrome (CSS). The co-occurrence of ARMs and CSS in an individual is unexpected since both disease are very rare. A review of the literature enabled us to identify 12 individuals with both CSS and ARMs. Among these 12 individuals, 9 had a variant in ARID1A, 2 in ARID1B, and 1 in SMARCA4. These data suggest a non-random association between CSS and ARMs, and indicate that ARMs is likely a rare feature of CSS.
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.
DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.
The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neurodevelopmental disorders. Other mouse models have addressed the influence of a homo- or heterozygous loss of Smarcb1, yet the impact of specific non-truncating mutations remains poorly understood. Here, we have established a new mouse model for the carboxy-terminal Smarcb1 c.1148del point mutation, which leads to the synthesis of elongated SMARCB1 proteins. We have investigated its impact on brain development in mice using magnetic resonance imaging, histology, and single-cell RNA sequencing. During adolescence, Smarcb11148del/1148del mice demonstrated rather slow weight gain and frequently developed hydrocephalus including enlarged lateral ventricles. In embryonic and neonatal stages, mutant brains did not differ anatomically and histologically from wild-type controls. Single-cell RNA sequencing of brains from newborn mutant mice revealed that a complete brain including all cell types of a physiologic mouse brain is formed despite the SMARCB1 mutation. However, neuronal signalling appeared disturbed in newborn mice, since genes of the AP-1 transcription factor family and neurite outgrowth-related transcripts were downregulated. These findings support the important role of SMARCB1 in neurodevelopment and extend the knowledge of different Smarcb1 mutations and their associated phenotypes.
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. This article is protected by copyright. All rights reserved.
Coffin‐Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non‐fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and a review of the literature, provide evidence that deleterious variants in ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, and SMARCC2, which are associated with CSS types 1–8, respectively, are associated with the development of CDH. This suggests that additional genetic testing to identify a separate cause of CDH in an individual with CSS may be unwarranted, and that comprehensive genetic testing for individuals with non‐isolated CDH should include an evaluation of CSS‐related genes. These data also suggest that the mSWI/SNF (BAF) complex may play an important role in diaphragm development.
