ACTG1 – Baraitser-Winter syndrome 2

Autosomal-dominant mutations in the γ-actin gene ACTG1 are implicated in Baraitser-Winter syndrome 2 (Baraitser-Winter syndrome 2). Clinical evidence includes an 18-year-old male and his brother presenting with global developmental delay, intellectual disability, lissencephaly, hearing impairment, and a broad nasal bridge. Trio-based exome sequencing identified a de novo missense variant, c.464C>T (p.Ser155Phe), segregating with disease in this family ([PMID:28496999]). To date, eight probands across seven families have been reported, all harboring heterozygous ACTG1 missense variants with autosomal-dominant inheritance.

Functional studies show that γ-actin is critical for nuclear DNA double-strand break repair by homologous recombination. Patient cells carrying ACTG1 mutations display homologous recombination defects comparable to NBS1 loss, implicating a dominant-negative effect on γ-actin–mediated DNA repair pathways ([PMID:40368919]). Together, the limited number of reported families and mechanistic data support a Limited clinical validity classification. Genetic testing for ACTG1 variants is recommended in individuals with Baraitser-Winter syndrome 2 features to guide diagnosis and counseling.

Key take-home: Screening for ACTG1 missense mutations enhances diagnostic accuracy for Baraitser-Winter syndrome 2.

References

• Journal of pediatric genetics • 2017 • The Clinical Manifestations and Genetic Implications of Baraitser-Winter Syndrome Type 2. PMID:28496999
• Nature communications • 2025 • Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin. PMID:40368919

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