Identification of a novel homozygous ARSG mutation as the second cause of Usher syndrome type 4

Abstract

Purpose: Usher syndrome is a genetic disease characterized by combined sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia, with 15 known causative genes. Depending on the severity and onset of the symptoms, 3 different subtypes of the pathology have been classically established, although an increasing number of rare cases are being accumulated as atypical forms. The present work aims to discover the genetic cause in a patient with atypical Usher syndrome, by performing whole exome sequencing in several family members.

Observations: The obtained results identified a novel homozygous missense mutation (p.Asp44Asn) in the ARSG gene as the cause of the disease, which was characterized by late-onset progressive symptoms in the patient. A resembling phenotype, recently defined as the novel Usher syndrome type 4, was described in three families sharing another ARSG mutation. Both mutations affect two contiguous amino acid residues, which appear to be critical for the correct function of the protein.

Conclusions and importance: These findings support the identification of the second disease mutation in this gene and a new evidence of the implication of ARSG in the genetic basis of Usher syndrome type 4.

Keywords: ARSG; Gene mutation; Retinitis pigmentosa; Sensorineural hearing loss; Usher syndrome type 4; Whole exome sequencing.

Fig. 1

Clinical evaluation of a patient with Usher syndrome type 4 presenting the homozygous c.130G>A pathogenic variant in ARSG. Right eye (left panels) and left eye (right panels) images of a 43-year-old patient: A, B) fundus retinographies show pink optic discs with only very mild pallor, normal appearing blood vessels and retinal pigment epithelium with disturbances, and bone spicule-like pigmentations in mid-periphery; C, D) fundus autofluorescence images present a hypoautofluorescent area at the level of the vascular arcades and a hyperautofluorescent ring surrounding the macular area; and E, F) automated perimetry reveals a bilateral visual field constriction with central preservation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)