Bi-Allelic MARVELD2 Variant Identified with Exome Sequencing in a Consanguineous Multiplex Ghanaian Family Segregating Non-Syndromic Hearing Loss

TL;DR

A harmful genetic variant in the MARVELD2 gene is linked to hearing loss in a Ghanaian family, with implications for inner ear function.

Contribution

A novel pathogenic MARVELD2 frameshift variant is identified as the cause of non-syndromic hearing loss in a consanguineous Ghanaian family.

Findings

A homozygous frameshift variant in MARVELD2 (c.1058dup) was found in all affected siblings.

The variant leads to a predicted loss of the conserved C-terminal domain and is targeted by nonsense-mediated decay.

Cell studies showed functional impacts on protein expression, localization, and actin cytoskeleton architecture.

Abstract

Genetic studies and phenotypic expansion of hearing loss (HL) for people living in Africa are greatly needed. We evaluated the clinical phenotypes of three affected siblings presenting non-syndromic (NS) HL and five unaffected members of a consanguineous Ghanaian family. Analysis of exome sequence data was performed for all affected and one unaffected family members. In-depth genetic and cellular characterization studies were performed to investigate biological significance of the implicated variant using bioinformatic tools and cell-based experimentation. Audiological examinations showed severe-to-profound, bilateral, symmetrical, and post-lingual onset. The whole-exome sequencing (WES) identified a homozygous frameshift variant: MARVEL domain containing 2 (MARVELD2):c.1058dup;p.(Val354Serfs*5) in all affected siblings. This frameshift variant leads to an early stop codon insertion and predicted to be targeted by nonsense medicated decay (mutant protein predicted to lack conserved C-terminal domain if translated). Cell immunofluorescence and immunocytochemistry studies exposed the functional impact of the mutant protein’s expression, stability, localization, protein–protein binding, barrier function, and actin cytoskeleton architecture. The identified variant segregates with NSHL in the index Ghanaian family. The data support this nonsense variant as pathogenic, likely to impact the homeostasis of ions, solutes, and other molecules, compromising membrane barrier and signaling in the inner ear spaces.

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