A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family

Abstract

Purpose: To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition.

Methods: A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing.

Results: The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment.

Conclusions: We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.

Figure 1

Co-segregation analysis of DFNB31 mutation in the consanguineous Portuguese family. Filled symbols represent the affected and the unfilled symbols represent the unaffected individuals. Squares depict males and circles depict females. Arrows mark the index patients. Equation symbols represent the unaffected alleles.

Figure 2

Sequence chromatographs for the novel homozygous mutation c.737delC found in exon 2 of DFNB31 of the index patient leading to a frameshift and premature stop codon p.Pro246HfsX13 and the respective control sequence below.

Figure 3

Ophthalmic phenotypic characterization of the right (OD) and left (OS) eye of the index patient. A: Color fundus photographs showing widespread changes in the midperiphery associated with atrophic changes in the macular area. B: Fundus autofluorescence imaging showing loss of autofluorescence in the midperiphery and in the perifoveal region. C: Sprectral domain optical coherence tomography of the right (OD) and left (OS) macula showing perifoveal thinning of the external layer of the retina.

Figure 4

Pure tone audiometry of the right (RE) and left (LE) ears showing bilateral moderately severe hearing loss at −63 dB for the RE and −53 dB for the LE. (○-) right and (x) left ear air conduction audiometry; (]- - -) right and ([- - - -) left ear bone conduction audiometry.