コフィン・シリス症候群

Coffin-Siris syndrome (CSS) (OMIM:614608) is a rare genetic disorder characterized by global developmental delay (GDD), speech impediment, coarse facial features, and hypoplastic or absent fifth fingernails/toenails. Genetic variants in the SMARCB1 gene are associated with CSS, benign tumors (schwannomas), and rhabdoid tumor predisposition syndrome. Genetic variants in the GNE gene are associated with the autosomal dominant sialuria (OMIM#269921), a rare inborn error of metabolism resulting in high levels of free sialic acid. Here we present case reports of two siblings: patient 1 (10 years) and patient 2 (2 years). While both siblings showed GDD and dysmorphic features such as hypotelorism and large ears, patient #1 exhibited additional phenotypes. Whole exome sequencing identified a heterozygous pathogenic variant, NM_003073.5:c.1096C>T (p.Arg366Cys), in the SMARCB1 gene in both siblings. In addition, patient 1 harbored a heterozygous likely pathogenic variant, NM_005476.7:c.2086G>A (p.Val696Met), in the GNE gene, which was absent in patient 2. The co-occurrence of the GNE variant may contribute to the increased severity of the phenotype in patient 1. This study is the first report worldwide of the co-occurrence of two extremely rare disorders. These findings highlight the complexity of genomic contributions while also emphasizing the value of genomic sequencing for congenital problems.

Coffin-Siris syndrome type 4 (CSS4; OMIM 614609) is a rare autosomal dominant disorder caused by variants in SMARCA4, encoding the BRG1 ATPase subunit of the BAF chromatin-remodeling complex. Although classically characterized by intellectual disability, distinctive facial features, and fifth digit hypoplasia, the phenotypic spectrum is broad and includes autism spectrum disorder (ASD) without typical somatic features. We report a 3-year-old Chinese girl with global developmental delay, ASD features, characteristic facial features, and a documented normal ophthalmologic examination in whom whole-exome sequencing identified a novel heterozygous de novo frameshift duplication, c.4767dup (p.Ser1590Ilefs*39), in SMARCA4 (NM_003072), classified as Pathogenic (PVS1+PM2_Supporting + PM6). Notably, she lacked fifth digit hypoplasia and had no structural ocular anomalies on detailed ophthalmologic evaluation. A systematic review of the literature identified 39 genetically confirmed SMARCA4-related CSS4 cases; combined with our patient, 40 cases were analyzed. Intellectual disability was universal (100%), ASD manifestations occurred in 42.5%, and fifth digit hypoplasia was present in only 55.0%. Truncating variants (37.5% of the cohort) showed descriptive trends toward higher prevalence of fifth digit hypoplasia and ocular abnormalities than missense variants, though these differences did not reach statistical significance. Our proband, despite carrying a truncating variant, presented without classic digital anomalies or ocular involvement, underscoring that even loss-of-function alleles can produce atypical CSS4 phenotypes. For children with developmental delay, ASD, and distinctive facial features-regardless of the presence of classic digital anomalies-genetic testing for SWI/SNF complex genes should be considered. Given current limited evidence, carriers of truncating variants should be counseled regarding potential tumor predisposition, and individualized surveillance strategies may be considered pending further data.

Arid1b is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex initially expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. Here, we used transgenic mice to investigate how Arid1b dysfunction in cortical excitatory neurons impacts their intrinsic membrane properties, synaptic connectivity and physiology of local cortical circuits using paired whole-cell recordings, social behavior, and seizure susceptibility. We found that loss of both copies of Arid1b altered the proportions of different excitatory neuron cell-types in the superficial cortical layers; however, their intrinsic membrane properties were mostly unchanged. In mice with conditional Arid1b haploinsufficiency in excitatory neurons, we found an increase in the rate of synaptic connectivity between excitatory neurons and reduced strength of excitatory synapses to parvalbumin (PV)-expressing inhibitory interneurons. In the deep cortical layers, we found hyperpolarization of action potential threshold. Collectively, these data suggest an increase in the ratio of excitation to inhibition. However, we also found enhanced inhibition from PV interneurons to excitatory neurons that may rebalance this ratio. Indeed, Arid1b haploinsufficiency in excitatory neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.

BACKGROUND: Coffin-Siris syndrome type 2 (CSS2), caused by ARID1A mutations, is characterized by neurodevelopmental delay and recurrent infections. The ARID1A p.Ala1077Glu variant has been linked to CSS2, but the immune mechanisms underlying infection susceptibility remain poorly understood. METHODS: The variant was identified by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Immune status was assessed via serum immunoglobulins, complement measurements, and flow cytometric immunophenotyping. RNA sequencing was performed on PMA-stimulated PBMCs from the patient and healthy controls, with key findings validated by qRT-PCR and ELISA. RESULTS: Immune profiling revealed widespread quantitative deficits across innate and adaptive compartments, with particularly marked reductions in NKT-like cells (CD3+CD56+) and CD8+ central memory T cells. Transcriptomic analysis of stimulated cells uncovered a profound activation defect, characterized by widespread downregulation of effector immune genes. Furthermore, pathway enrichment analysis demonstrated significant suppression of multiple biological processes critically dependent on IFN-γ signaling, such as antigen processing and presentation, and Th1/Th17 cell differentiation. Expression of IFNG, STAT1, and CXCL9 showed a trend toward decreased expression. CONCLUSION: Our findings suggest an association between the ARID1A p.Ala1077Glu variant and impaired IFN-γ-mediated immunity in CSS2, potentially contributing to recurrent infections. The IFN-γ pathway warrants further investigation as a therapeutic target.

Evaluating the impact of genomic variation is essential for identifying underlying mechanistic causes of human diseases. The spectrum of neurodevelopmental disorders is driven by diverse genetic alterations with genes like SMARCA4 being prototypical examples. There have been significant hurdles to implementing the protein-specific and mechanism-informed variation effect predictors that are anticipated to have the highest yield of mechanistic information. Yet, there is a pressing need, for example, within SMARCA4 where 98% of the 2780 reported variants lack a disposition and remain of uncertain significance (VUS). Further, the field has yet to identify each variant's specific molecular mechanism, which will inform targeted therapeutic development strategies. In this study we developed a mechanistic structure-informed helicase-specific variant effect predictor by leveraging diverse information with state-specific calculations. Our approach has 100% recall of pathogenic variants while classifying 87.23% of VUS into damaging (55.74%, n=262) versus tolerated effects (31.49%, n=148), including those with conflicting interpretations. This analysis reveals significant enrichment of integrated functional metrics, such as conservation and solvent exposure, that parallel allele frequences in health populations, and emphasizes the robustness of the method. Thus, we have demonstrated a novel approach for the development of mechanism-informed protein-specific interpretation of human genetic information.