Pathogenic variants in SHROOM3 associated with hemifacial microsomia

Area of Science:

• Genetics
• Developmental Biology
• Medical Research

Background:

• Hemifacial Microsomia (HFM) is a rare congenital disorder impacting facial symmetry and development.
• Known genetic causes explain only a small fraction of HFM cases, necessitating further gene discovery.

Purpose of the Study:

• To investigate the role of the SHROOM3 gene in the etiology of Hemifacial Microsomia.
• To identify novel pathogenic variants in SHROOM3 associated with HFM.

Main Methods:

• Genome-wide association studies and gene burden analysis were performed on HFM patients.
• Deleterious SHROOM3 variants were identified and functionally evaluated.
• SHROOM3 expression patterns and effects of gene editing in mice were examined.

Main Results:

• Common variants in SHROOM3 showed association with HFM, and rare variants were significantly enriched in HFM patients.
• Seven deleterious SHROOM3 variants were found in Chinese HFM patients, suggesting dominant inheritance with incomplete penetrance.
• SHROOM3 expression in pharyngeal arches and facial abnormalities in gene-edited mice support its role in facial development.

Conclusions:

• SHROOM3 is implicated as a likely pathogenic gene contributing to Hemifacial Microsomia.
• The findings expand the genetic understanding of HFM and highlight SHROOM3 as a potential therapeutic target.