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Coffin-Siris syndrome (CSS) is a rare autosomal dominant neurodevelopmental disorder characterized by developmental delay, intellectual disability, hypoplastic nails, microcephaly, coarse facial features, and growth deficiency. SOX11 (HGNC:11191), a downstream transcription factor of the BAF chromatin-remodeling complex, was first implicated in CSS through trio exome sequencing identifying de novo missense variants in two unrelated individuals with mild CSS phenotypes (PMID:24886874). Subsequent reports have described additional de novo and inherited SOX11 variants in patients exhibiting core CSS features, expanding both the genotypic and phenotypic spectrum.
Genetic evidence supports an autosomal dominant inheritance mode for CSS9. To date, at least 19 unrelated probands across ten independent studies have been reported with heterozygous SOX11 variants, including 10 protein-truncating (nonsense/frameshift) and >9 missense alterations affecting the HMG domain and non-HMG regions (PMID:26543203; PMID:31530938). Segregation of a missense c.139G>A (p.Gly47Ser) variant in a mother and her two daughters confirms familial transmission (PMID:33785884). Recurrent variants, such as c.305C>T (p.Ala102Val), have been observed in multiple patients, suggesting mutational hotspots (PMID:28787104).
Variant spectrum includes missense (≥9), loss-of-function (≥10), and small structural deletions (n=7) disrupting SOX11. Clinical features common to SOX11-related CSS include intellectual disability (HP:0001249), microcephaly (HP:0000252), hypoplastic nails (HP:0001792), growth delay (HP:0001510), and global developmental delay (HP:0001263). A novel feature of sensorineural hearing loss has been reported in two Chinese probands with de novo variants c.150G>T (p.Lys50Asn) and c.811_814del (p.Asn271SerfsTer10) (PMID:36369738).
Functional studies demonstrate haploinsufficiency as the pathogenic mechanism. Sox11 knockdown in zebrafish and Xenopus reproduces microcephaly and brain malformations, and rescue experiments confirm specificity (PMID:24886874; PMID:26543203). Human SOX11+/- hESC models show impaired neuronal differentiation and increased cell death, corroborating in vivo findings (PMID:31035284). Reporter assays for missense variants reveal markedly reduced transactivation of downstream targets such as GDF5 and FGF9, aligning with craniofacial and limb phenotypes.
No studies have disputed the link between heterozygous SOX11 variants and CSS; however, overlapping presentations with Pitt-Hopkins syndrome-like features suggest phenotypic heterogeneity rather than conflict. Recent large-scale cohort data underscore that SOX11-related CSS constitutes a distinct BAFopathy with a characteristic clinical and episignature profile (PMID:35341651).
Integration of genetic and experimental data supports a Definitive gene–disease association between SOX11 and Coffin-Siris syndrome. De novo and familial variants co-segregate with disease, meet genetic caps, and align with robust functional concordance in multiple models. Key Take-home: Heterozygous loss-of-function and missense variants in SOX11 cause autosomal dominant Coffin-Siris syndrome, warranting inclusion of SOX11 in diagnostic gene panels for neurodevelopmental disorders.
Gene–Disease AssociationDefinitive19 probands across ten unrelated families, multiple de novo variants and three segregations, concordant functional data Genetic EvidenceStrong10 protein-truncating and ≥9 missense variants in >19 probands; segregation and recurrent hotspots Functional EvidenceModerateZebrafish, Xenopus knockdown and hESC haploinsufficiency models recapitulate CSS phenotypes; rescue and reporter assays confirm LOF |