A novel mutation in ACTG1 causing Baraitser-Winter syndrome with extremely variable expressivity in three generations

Area of Science:

• Genetics
• Developmental Biology
• Ophthalmology

Background:

• Baraitser-Winter syndrome is a rare developmental disorder characterized by facial anomalies, brain malformations, and other systemic issues.
• It is typically caused by mutations in ACTB or ACTG1, genes encoding actin proteins, with previously reported cases arising from new mutations.
• Isolated non-syndromic hearing loss has also been linked to ACTG1 mutations, often with autosomal dominant inheritance.

Purpose of the Study:

• To investigate a novel mutation in the ACTG1 gene within a three-generation family.
• To describe the variable expressivity of Baraitser-Winter syndrome and its potential misdiagnosis as isolated hearing loss.
• To document previously unreported subtle optic nerve signs associated with this syndrome.

Main Methods:

• Genetic analysis of a three-generation pedigree.
• Clinical evaluation of affected individuals, including ophthalmological examinations.
• Phenotypic characterization of Baraitser-Winter syndrome and comparison with previously reported cases.

Main Results:

• Identification of a novel, segregating mutation in the ACTG1 gene responsible for Baraitser-Winter syndrome.
• Demonstration of extreme variable expressivity, with two family members initially diagnosed with isolated autosomal dominant hearing loss.
• Documentation of subtle optic nerve abnormalities in one patient, a finding not previously reported in Baraitser-Winter syndrome.

Conclusions:

• Novel ACTG1 mutations can cause Baraitser-Winter syndrome with significant phenotypic variability.
• Variable expressivity may lead to misdiagnosis, highlighting the importance of comprehensive genetic and clinical evaluation.
• The identification of subtle optic nerve signs expands the known clinical spectrum of Baraitser-Winter syndrome.