コフィン・シリス症候群

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.

PURPOSE: Variants in SMARCB1, encoding a core subunit of the BAF (ie, BRG/BRM-associated factor) chromatin remodeling complex, are associated with intellectual developmental disorders, particularly Coffin-Siris syndrome, although the genotype-phenotype spectrum remains incompletely defined. This study aims to assess the correlations between SMARCB1 variant location and phenotypic manifestations. METHODS: We analyzed 31 individuals with pathogenic or likely pathogenic SMARCB1 variants using multimodal approaches, integrating clinical, structural, and machine learning analyses. We predicted variant effects via 3-dimensional protein modeling, assessed facial similarity using GestaltMatcher, and conducted phenotype-driven genotype prediction using machine learning classifiers. RESULTS: Variants clustered within the N-terminal (winged-helix/SNF5) and C-terminal (αC-helix) regions. C-terminal Coffin-Siris syndrome variants were associated with more severe speech delay, microcephaly, and cleft palate, exhibiting stronger facial gestalt similarity. XGBoost achieved 96.7% accuracy in classifying variant location from phenotype alone. Although gestalt is a key feature delineating variants at the αC helix, overall clinical features have greater predictive power for N-terminal variants. CONCLUSION: Using detailed phenotyping and machine learning algorithms, we identified differences between individuals with N-terminus and C-terminus SMARCB1 variants. Our study underscored the importance of multimodal assessments for genotype-phenotype associations, suggesting that integrated modeling can provide insights into SMARCB1 variant effects and biological function, with the potential for improvement in diagnostic strategies.

Pathogenic variants in BAF complex genes are linked to neurodevelopmental disorders, termed BAFopathies. Coffin-Siris syndrome (CSS) is the most well-defined BAFopathy caused by variants in several BAF subunit genes. ARID1A variants are responsible for 6-8% of CSS cases. We report a female individual with clinical and phenotypic manifestations suggestive of CSS. Trio exome sequencing failed to identify a causative variant. Short-read genome sequencing revealed a de novo 24 kb intronic deletion in ARID1A. Methylation analysis showed a BAFopathy-like profile supporting pathogenicity. Transcriptome analysis and RT-PCR detected a rare aberrant splicing event in a subset of ARID1A transcripts: the activation of a pseudoexon, resulting in a premature termination codon as the underlying pathomechanism. This is the first non-coding pathogenic alteration reported in ARID1A and the second in a CSS gene. This case highlights how the combination of genomic, transcriptomic and epigenomic data is crucial to improve diagnostic accuracy in unsolved cases.

BACKGROUND: SOX11 variants have been associated with Coffin-Siris syndrome and a broader neurodevelopmental spectrum (IDDMOH), but their role in isolated or syndromic hypogonadotropic hypogonadism (HH) remains under-recognized. CASE PRESENTATION: We report a 13-year-old Chinese girl who presented with delayed puberty (Tanner B1, PH1), infantile uterus and low basal gonadotropins. Trio whole-exome sequencing identified a de-novo heterozygous SOX11 c.346_348del (p.Tyr116del) variant. Olfactory and pituitary MRI revealed bilateral olfactory-bulb/nerve hypoplasia and a pituitary height of 3.4 mm, fulfilling Kallmann-syndrome criteria. GnRH-pump therapy restored gonadotropin output within 72 h. A systematic literature review of 32 additional SOX11-related HH cases (total n = 33) showed that 25/26 phenotyped individuals exhibited Coffin-Siris-compatible features, whereas 13/33 met Kallmann-syndrome criteria. Thirty unique variants were identified, 17/30 clustering within the HMG domain and 15/18 proven de-novo. CONCLUSIONS: SOX11 should be included in Kallmann syndrome gene panels. We propose "SOX11-related disorder" as an overarching diagnostic framework for all individuals with SOX11 likely pathogenic/pathogenic variants, mandating comprehensive baseline evaluation-including endocrine assessment, neurodevelopmental screening, and MRI of olfactory tracts and pituitary-regardless of initial presentation.

The phenotypic spectrum associated with pathogenic ARID1B variants is remarkably broad, ranging from classic Coffin-Siris syndrome to non-syndromic intellectual disability and autism spectrum disorders. While speech delay, motor impairments and learning difficulties are well documented, brain imaging investigations remain scarce in this population. We combined multimodal neuroimaging and neuropsychological assessments in 12 patients carrying pathogenic ARID1B variants (age = 13.8 ± 4.7 years) and 34 age-matched healthy controls. Whole-brain voxel-wise analyses included arterial spin labelling to measure cerebral blood flow (CBF) at rest and voxel-based morphometry to assess grey matter density. To investigate white matter abnormalities, we performed fixel-based analysis in a subgroup of 7 patients and 17 age-matched controls. While patients showed pronounced language, motor and social impairments, their memory performance ( + 5 SD) largely exceeded other cognitive and motor skills. Whole-brain voxel-wise analyses showed a significant bilateral increase of CBF at rest in several limbic structures, including hippocampi and visual areas. They also showed significant decrease in grey matter density and fibre density in the same limbic structures, language, motor and social circuits. This paradoxical coexistence of hyperperfusion and structural deficits within memory networks suggests functional resilience or compensatory mechanisms. These preserved visual and memory functions strongly contrasted with their impaired language, motor, and social abilities. Patients appeared to rely on visual cues and memory to compensate for deficits in verbal communication. These findings support the development of individualized and innovative interventions that build on preserved visual and memory abilities in children with pathogenic ARID1B variants.