First reports of fetal SMARCC1 related hydrocephalus

Gouard, Nicolas Rive Le; Nicolle, R; Lefebvre, Mathilde; Gelot, Antoinette; Heide, Solveig; Герасименко, А. В.; Grigorescu, R; Derive, Nicolas; Jouannic, Jean‐Marie; Garel, Catherine; Valence, Stéphanie; Quenum-Miraillet, Geneviève; Chantot‐Bastaraud, Sandra; Keren, Boris; Héron, Delphine; Attié‐Bitach, Tania

doi:10.1016/j.ejmg.2023.104797

Cited by 2 publications

(1 citation statement)

References 28 publications

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“…One variant was associated with additional brain malformations, including gyration delay and abnormal aspect of frontal horns. In addition, abnormalities were noted in other systems, including renal and skeletal malformations 7 . Overall, our and previous reports suggest that SMARCC1 haploinsufficiency is not only associated with hydrocephalus due to aqueduct stenosis, but also with other central nervous system (CNS) and non‐CNS malformations.…”

Section: Discussionsupporting

confidence: 69%

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance

Hourvitz,

Kurolap,

Mory

et al. 2023

Prenatal Diagnosis

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A Jewish couple of mixed origin was referred for genetic counseling following termination of pregnancy at 18 weeks of gestation due to severe ventriculomegaly with aqueduct stenosis. Trio exome sequencing revealed a loss‐of‐function heterozygous variant in the SMARCC1 gene inherited from an unaffected mother. The SMARCC1 gene is associated with embryonic neurodevelopmental processes. Recent studies have linked perturbations of the gene with autosomal dominant congenital hydrocephalus, albeit with reduced penetrance. However, these studies were not referenced in the SMARCC1 OMIM record (*601732) and the gene was not considered, at the time, an OMIM morbid gene. Following our case and appeal, SMARCC1 is now considered a susceptibility gene for hydrocephalus. This allowed us to reclassify the variant as likely pathogenic and empowered the couple to make informed reproductive choices.

show abstract

Section: Discussionsupporting

confidence: 69%

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance

Hourvitz,

Kurolap,

Mory

et al. 2023

Prenatal Diagnosis

View full text Add to dashboard Cite

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A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus

Singh,

Allington,

Viviano

et al. 2023

Brain

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Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodeling complex, as a candidate congenital hydrocephalus (CH) gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, CH-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of CH. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2,697 total ventriculomegalic trios, including patients with neurosurgically-treated CH, that total 8,091 exomes collected over 7 years (2016-2023). A comparison control cohort consisted of 1,798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons simplex consortium. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization, and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare protein-altering de novo variants (DNVs) localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest DNVs in SMARCC1 cause a novel human BAFopathy we term “SMARCC1-associated Developmental Dysgenesis Syndrome (SaDDS)”, characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, DD, and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodeling complex for human brain morphogenesis and provide evidence for a “neural stem cell” paradigm of CH pathogenesis. These results highlight utility of trio-based WES for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest WES may be a valuable adjunct in clinical management of CH patients.

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First reports of fetal SMARCC1 related hydrocephalus

Cited by 2 publications

References 28 publications

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance

SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus

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