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ARID2 encodes a core subunit of the BAF (SWI/SNF) chromatin remodeling complex, and heterozygous ARID2 variants are the established cause of Coffin-Siris syndrome 6, a multisystem developmental disorder characterized by global developmental delay, coarse facial features, digital hypoplasia, and ectodermal anomalies ([PMID:35813374]). Until recently, only 16 individuals had been reported with pathogenic ARID2 variants including missense, nonsense, frameshift, and splice-site changes ([PMID:35813374]). Microdeletions encompassing the entire ARID2 locus have been predicted to cause loss of function equivalent to null alleles but were previously rare.
A 2023 study identified a de novo 1.563 Mb heterozygous deletion of the ARID2 locus in a 5-year-7-month-old female presenting with severe short stature, global developmental delay, hypoplastic fingers and toes, and dysmorphic facial features ([PMID:36756859]). Endocrine evaluation revealed normal growth hormone levels with reduced IGF-1 and elevated CA19-9. This microdeletion expanded the number of documented ARID2-deficient patients to 27 unrelated probands ([PMID:36756859]). The consistent phenotype across deletion and sequence variants underscores a shared haploinsufficiency mechanism.
Sequence variants reported to date include truncating alleles predicted to trigger nonsense-mediated decay, distributed throughout ARID2 without apparent domain clustering. No recurrent or founder variants have been observed. All described variants are heterozygous and de novo, supporting an autosomal dominant inheritance model. The absence of biallelic or homozygous variants in population databases further corroborates haploinsufficiency. Prevalence and carrier frequency remain undefined due to the rarity of cases.
Among the 27 ARID2-deficient individuals, key clinical features include severe short stature (HP:0003510), global developmental delay (HP:0001263), coarse facial features (HP:0000280), sparse scalp hair (HP:0002209), hypertrichosis (HP:0000998), and digital hypoplasia. A retrospective review demonstrated a significant positive correlation between age and height standard deviation score (r = 0.71, p = 0.0002), suggesting potential for growth catch-up over time ([PMID:36756859]). Variable findings such as feeding difficulties, cardiac anomalies, and tumor marker elevations (e.g., CA19-9) have also been noted.
Segregation analysis includes one multiplex family showing variable expressivity among affected relatives, supporting autosomal dominant inheritance and full penetrance for loss-of-function alleles ([PMID:35813374]). No unaffected carriers have been described. All sequenced trios have revealed de novo variants, providing strong genetic evidence. One additional affected relative was documented in a single pedigree.
Direct functional studies of ARID2 haploinsufficiency in cellular or animal models have not yet been reported, representing a gap in experimental validation. Nevertheless, the convergence of de novo heterozygous loss-of-function variants, uniform clinical phenotype across unrelated individuals, and segregation in a family provides strong evidence for a haploinsufficiency mechanism. Clinically, ARID2 testing should be included in genetic workup of patients with Coffin-Siris-like features to guide anticipatory growth monitoring, genetic counseling, and management. Given evidence for partial growth catch-up, longitudinal height surveillance is recommended.
Gene–Disease AssociationStrong27 unrelated probands with de novo heterozygous ARID2 variants across two studies; consistent phenotype and segregation in one family. Genetic EvidenceStrong27 de novo loss-of-function variants in unrelated probands with phenotypic concordance and segregation in one family. Functional EvidenceLimitedNo functional assays or animal models directly assessing ARID2 haploinsufficiency reported. |