RESUMEN
ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis.
Asunto(s)
Proteínas de Unión al ADN , Cara , Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Cuello , Factores de Transcripción , Humanos , Discapacidad Intelectual/genética , Micrognatismo/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Deformidades Congénitas de la Mano/genética , Cuello/anomalías , Cara/anomalías , Anomalías Múltiples/genética , Mutación , Masculino , Agregado de ProteínasRESUMEN
Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.
Asunto(s)
Anomalías Múltiples , Cara/anomalías , Deformidades Congénitas de la Mano , Discapacidad Intelectual , Micrognatismo , Adulto , Humanos , Niño , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico , Micrognatismo/genética , Micrognatismo/diagnóstico , Deformidades Congénitas de la Mano/genética , Cuello/anomalías , Fenotipo , ADN Helicasas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genéticaRESUMEN
PURPOSE: Botulinum toxin injections in the anal sphincter apparatus (Botox) and enteral neuromodulation (ENM) are options for treatment of refractory chronic constipation. We present a retrospective comparative observational study. PATIENTS AND METHODS: From 2014 to 2022, pediatric patients with chronic constipation were either treated with Botox or ENM with continuation of conservative treatment. Comparison was conducted regarding the primary outcome variables defecation frequency, stool consistency, and abdominal pain. Secondary outcomes were fecal incontinence, enuresis, change of medication and safety of treatment. RESULTS: 19 Botox patients (10 boys, 9 girls, 12 patients with Hirschsprung disease (HD), 7 patients with functional constipation (FC)) were compared to 24 ENM patients (18 boys, 6 girls, 12 HD patients, 7 FC patients). Groups differed significantly in age (5.0 years (Botulinum toxin) and 6.5 years (ENM), mean values, p-value 0.008). Improvement of constipation was seen in 68% (n = 13/19) of Botox and 88% (n = 21/24) of ENM patients (p = 0.153). Influence of etiology on therapeutic effects was not observed. Complications were minor. CONCLUSIONS: Botox and ENM can be considered as valuable and effective treatment options in refractory chronic constipation. Prospective, large-population studies should be designed to enable improved evidence.