Abstract
Purpose :
Mutations in USH2A, encoding usherin, are the most common cause for non-syndromic autosomal recessive retinitis pigmentosa (RP) and Usher syndrome type 2. Here we report two siblings with extremely mild forms of retinitis pigmentosa without hearing impairment, each confirmed to be compound heterozygous for an USH2A c.6590C>T missense variant and an exon 70 deletion.
Methods :
Each patient underwent clinical examination, microperimetry, OCT, fundus autofluorescence (FAF) imaging, and genetic testing by targeted next generation sequencing.
Results :
Two sisters, aged 50 and 48 years, presented with slow, progressive peripheral visual field loss and nyctalopia beginning in their 30s. They were otherwise clinically well, had no hearing deficit on audiology testing, and no family history of any vision problems. Cancer-related retinopathy had been excluded. Visual acuities were 6/5 OD 6/6 OS in the elder and 6/6 OU in the younger, both retaining sufficient visual fields for driving. FAF in both patients showed a hyperautofluorescent ring surrounding the macula bilaterally. OCT demonstrated well-preserved retina within the ringed areas, but ellipsoid zone loss outside the ring. Genetic testing of the older sister initially found a heterozygous missense variant of uncertain significance, USH2A c.6590C>T (Thr2197Ile). Multiplex ligand-dependent probe amplification (MLPA) analysis revealed heterozygosity for an exon 70 deletion, predicted to result in a frameshift. Genetic testing of the younger sister showed identical mutations. Further segregation analysis confirmed bi-allelic inheritance.
Conclusions :
Compound heterozygosity of a missense mutation and a 3’ exon deletion in USH2A is associated with a very mild form of RP with preserved central vision and hearing. USH2A c.6590C>T was previously reported as a variant of uncertain significance with conflicting evidence of pathogenicity. Deletion of the penultimate exon 70 is predicted to cause read-through of the terminal splice site into terminal exon 72 before reaching a stop codon. While this transcript may evade nonsense-mediated decay, disruption of the C-terminus may affect the PDZ-binding motif (PBD) and its interaction with harmonin. While there remains some uncertainty regarding the pathogenicity of c.6590C>T variant, the mild phenotypes observed would be compatible with partially retained protein function.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.