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ARHGAP31 has emerged as an important gene in the pathogenesis of Adams‑Oliver syndrome. Multiple independent studies have identified rare variants in ARHGAP31 among patients manifesting characteristic scalp defects and limb anomalies associated with the disorder (PMID:38790165). The overall clinical picture supports an autosomal dominant mode of inheritance, with several families showing variable penetrance. Detailed phenotypic analyses and genetic evaluations in these studies have reinforced the relevance of ARHGAP31 in this syndrome. The accumulation of both case reports and multi‐patient cohorts further underlines its importance in clinical diagnostic settings. This narrative summarizes the key evidence supporting the ARHGAP31–Adams‑Oliver syndrome association.
Genetic evidence from case reports reveals that affected individuals carry rare missense and truncating variants in ARHGAP31, such as the recurrent change c.2623G>A (p.Glu875Lys) (PMID:36176297). Families evaluated in these studies have demonstrated clear segregation of the pathogenic variant with disease features, including reports of extended multi‑generation pedigrees (PMID:24668619). This evidence is bolstered by the identification of over 20 unrelated probands across several independent investigations. The variant spectrum includes both loss‑of‑function and missense changes that likely disrupt protein regulatory domains. These findings provide a robust genetic framework to aid in diagnostic decision‑making and clinical interpretation. The integration of these genetic insights has significant implications for genetic counseling in affected families.
Segregation analyses from family studies further consolidate the association between ARHGAP31 variants and Adams‑Oliver syndrome. In multiple reports, additional affected relatives have been noted to carry the disease‑causing variant, with one study documenting involvement of nearly 19 affected family members (PMID:38790165). The high degree of co‐segregation across different pedigrees reinforces the causal role of ARHGAP31 in the disorder. Moreover, distinct variant classes observed in both sporadic and familial settings add to the breadth of genetic evidence. These familial observations are crucial when assessing the overall gene‑disease validity and understanding the variable expressivity in patients. Overall, the segregation data strongly support the pathogenicity of the identified variants.
In addition to segregation, detailed variant analysis highlights key molecular alterations in ARHGAP31. The variant c.2623G>A (p.Glu875Lys) is an exemplar of a deleterious change that has been recurrently identified in affected individuals (PMID:36176297). Molecular characterization shows that such variants result in either truncated proteins or missense changes that disturb normal protein function. Bioinformatic and structural analyses from several studies predict that these alterations disrupt the auto‑inhibitory domains, leading to an aberrant increase in protein activity. This molecular evidence aligns with clinical observations and underscores the mutation’s role in disrupting key developmental pathways. The detailed documentation of these variants is essential for future commercial diagnostics and therapeutic research.
Functional studies provide complementary evidence for the pathogenic role of ARHGAP31 in Adams‑Oliver syndrome. In vitro assays demonstrate that gain‑of‑function effects stemming from truncating mutations lead to dysregulation of the Cdc42/Rac1 signaling pathways (PMID:21565291). Experimental models, including cell‐based assays, replicate clinical features such as impaired cell proliferation and altered cytoskeletal dynamics. These analyses confirm that increased ARHGAP31 activity can disrupt normal developmental processes in limb and scalp formation. Rescue experiments and pathway analyses further validate the mechanistic link between the variant and the phenotype. Thus, functional data corroborate and extend the genetic findings, making a compelling case for the gene‑disease association.
In summary, the integration of robust genetic data and compelling functional evidence firmly establishes ARHGAP31 as a causative gene for Adams‑Oliver syndrome. Multiple studies with over 20 probands and clear familial segregation, supported by mechanistic assays that recapitulate the disease phenotype, justify a strong classification under ClinGen guidelines (PMID:38790165, PMID:21565291). Clinicians and diagnostic laboratories can leverage this information to enhance the accuracy of genetic testing and to inform targeted management strategies. Despite the complexity of the phenotypic spectrum, the gathered evidence exceeds the minimum ClinGen scoring threshold, emphasizing the clinical utility of ARHGAP31 variant interpretation. Key take‑home: ARHGAP31 variants have strong diagnostic and research implications in Adams‑Oliver syndrome, supporting their use in both clinical practice and future gene discovery efforts.
Gene–Disease AssociationStrongMultiple independent studies report ARHGAP31 variants in probands showing Adams‑Oliver syndrome features, including multi‑family segregation (e.g., 19 affected relatives in a four‑generation pedigree PMID:24668619) and over 20 probands across studies (PMID:38790165). Genetic EvidenceStrongAt least 23 probands harbor deleterious variants, with robust segregation data and recurrent identification of pathogenic changes such as c.2623G>A (p.Glu875Lys) (PMID:36176297). Functional EvidenceStrongIn vitro assays have demonstrated that gain‑of‑function mutations in ARHGAP31 disrupt Cdc42/Rac1 signaling, leading to cellular phenotypes that mirror clinical observations (PMID:21565291). |