GNAI3 – Auriculocondylar Syndrome

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder characterized by a distinctive clinical triad of question mark ears, mandibular condyle hypoplasia, and micrognathia. Recent case reports and multi‐patient studies have consistently implicated mutations in GNAI3 as causative for this syndrome (PMID:39014351).

Assessment of clinical validity for the GNAI3–ACS association falls in the Strong range according to ClinGen criteria. Multiple independent studies have identified pathogenic variants in unrelated probands, with familial segregation documented—for instance, a Chinese family exhibited the mutation in both the proband and an affected sibling (PMID:39014351). Functional assays further corroborate the pathogenic mechanism by demonstrating a dominant negative effect on the protein’s GDP/GTP binding function (PMID:25026904).

From a genetic standpoint, the inheritance mode in documented cases is predominantly autosomal dominant. Segregation analysis in familial cases has revealed at least one additional affected relative sharing the variant, supporting a robust genetic contribution. Across the literature, several variant types have been reported, predominantly missense and insertion events that alter critical functional motifs of the GNAI3 protein.

Specifically, the reported variant c.144_145insCATTGTGAAACAGATGAA (p.Thr48_Ile49insHisCysGluThrAspGlu) is representative of the insertion mutations identified in ACS patients. This variant disrupts protein function by interfering with nucleotide binding, a finding that is consistent across multiple cohorts and experimental models (PMID:22560091).

Functional studies, including in vitro assays and protein-structure analyses, support a mechanism of pathogenicity via a dominant negative effect. These experimental assessments show a significant reduction in downstream signaling activity, which aligns with the craniofacial abnormalities observed in affected individuals (PMID:27072656).

In conclusion, the integration of genetic and experimental evidence robustly supports the association between GNAI3 mutations and auriculocondylar syndrome. The strong mechanistic concordance and segregation data highlight the clinical utility of genetic testing in diagnosing ACS, thereby guiding precision management in affected patients.

References

• BMC oral health • 2024 • Novel GNAI3 mutation in a Chinese family with auriculocondylar syndrome and treatment of severe dentofacial deformities: a 5-year follow-up case report PMID:39014351
• American journal of human genetics • 2012 • A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome PMID:22560091
• European journal of human genetics • 2015 • Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect PMID:25026904
• Science signaling • 2016 • Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease PMID:27072656

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