Evolutionary Landscape of SOX Genes to Inform Genotype-to-Phenotype Relationships.

Area of Science:

• Genetics and Developmental Biology
• Molecular Biology
• Human Genetics

Background:

• The SOX (SRY-related HMG-box) transcription factor family plays a critical role in regulating developmental processes.
• Understanding genotype-phenotype relationships in SOX proteins is crucial for diagnosing and treating associated congenital disorders.

Purpose of the Study:

• To conduct a non-biased investigation of SOX gene variants to establish robust genotype-phenotype associations.
• To identify specific amino acid changes within SOX proteins linked to clinical pathologies and developmental abnormalities.

Main Methods:

• Analysis of 1890 SOX open-reading frames and 6667 amino acid sequences.
• Integration of structural dynamics with variant data from gnomAD, ClinVar, Geno2MP, and COSMIC databases.
• Screening of identified variants against medical phenotypes in Geno2MP.

Main Results:

• Identified 27 amino acid sites within the High Mobility Group (HMG)-box showing changes across multiple SOX proteins linked to clinical pathologies.
• Discovered novel associations: SOX15 R104G with musculature abnormality, SOX8 R159G with intellectual disability, and SOX18 E137K with neurological complications.
• Found 56 conserved variants outside the HMG-box, including SOX9 variants linked to Campomelic Dysplasia and SOX7 variants associated with eye phenotypes.

Conclusions:

• This comprehensive compilation of SOX data establishes strong genotype-to-phenotype associations for the SOX gene family.
• The findings provide valuable insights into the molecular basis of developmental disorders linked to SOX protein dysfunction.
• Highlights the importance of integrating diverse genetic and clinical datasets for accurate variant interpretation.