SOXopathies: Growing Family of Developmental Disorders Due to SOX Mutations

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• The SRY-related (SOX) transcription factor family is crucial for cell fate determination.
• Mutations in SOX genes lead to rare congenital disorders known as SOXopathies.
• SOXopathies are typically caused by heterozygous, de novo, inactivating mutations, indicating gene haploinsufficiency.

Purpose of the Study:

• To review the clinical and molecular characteristics of SOXopathies.
• To explore the potential for additional SOX genes to be implicated in SOXopathies.
• To discuss the expanding spectrum of clinical and genetic presentations associated with SOXopathies.

Main Methods:

• Literature review of clinical and molecular data on SOXopathies.
• Analysis of mutation types, including deletions, duplications, and missense variants.
• Focus on the HMG domain's role in SOX gene function and disease pathogenesis.

Main Results:

• Half of the 20 human SOX genes have been linked to SOXopathies.
• Missense variants frequently affect the HMG domain, crucial for DNA binding and protein interactions.
• SOXopathies exhibit diverse genetic mechanisms beyond simple gene deletions.

Conclusions:

• SOXopathies represent a growing group of genetic disorders linked to SOX gene dysfunction.
• The HMG domain is a key target for pathogenic variants in SOXopathies.
• The full extent of SOX gene involvement and the clinical spectrum of SOXopathies are likely underestimated.