Extreme Phenotypic Variability of ACTG1-Related Disorders in Hearing Loss

Abstract

Hearing loss is the most common sensory defect in humans, affecting normal communication. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors, but single-gene mutations can lead to syndromic or non-syndromic hearing loss. Monoallelic variants in ACTG1, coding for gamma (γ)-actin, are associated with classical Baraitser-Winter Syndrome type 2 (BRWS2, nonsyndromic deafness, and a variety of clinical presentations not fitting the original BRWS2 description or nonsyndromic deafness. Here two unrelated patients with ACTG1 variants are reported, having severe hearing loss as a common phenotype but with different clinical presentations, supporting the extreme variability of ACTG1-related disorders.

Keywords: ACTG1; hearing loss.

Figure 1

Clinical and molecular evaluation of hearing loss patients A) Pedigrees of affected individuals (marked with arrows). Age is shown for the patients on their first visit. B) Tone audiometry, Suzuki–Ogiba test^{[ 25 ]} Black rectangles: Overall hearing, for Patient 1 and Pure‐tone audiometry (Red circles: Right ear; Blue crosses: Left ear) for Patient 2 are depicted. Both audiograms are faithful copies of the original studies. C) In silico modeling of the variants. 3D Structural visualization of γ‐actin. The image shows the monomer chain B, with the Ile165 in magenta, and molecular surface representation colored by chemical classification of residues; hydrophobic (white), hydrophilic (green), positive charged (blue), and negative charged (red). D) Dimer Chain C and D, Pro 258 (green) and Pro264 (blue). These two prolines are responsible for the loop that presumably stabilizes the dimer by interacting with the neighbor chain. In both cases, zoom‐in shows the reference residue and the type of interactions with their neighbor residues; polar (orange), hydrophobic (green), hydrogen bond (red), and clash (pink).