Mutations in CDH23 are notable for phenotypically heterogeneous outcomes, including Usher syndrome type 1D (USH1D) and a form of nonsyndromic deafness (DFNB12).1–3 Usher syndrome type 1 (USH1) is the most severe subtype of Usher syndrome and presents with deafness, retinitis pigmentosa (RP), and early-onset vestibular dysfunction. In USH1D, common ophthalmic findings include nyctalopia, peripheral visual field loss, diffuse RP, optic nerve pallor, and arterial narrowing.2 DFNB12 is an autosomal recessive type of severe bilateral, prelingual, nonsyndromic hearing loss. It has been shown that the type of CDH23 mutation differentiates between these two phenotypes due to the varying degree of protein dysfunction resulting from each mutation type.1–3
Here, we present a patient with congenital deafness and sector RP who was found to be a compound heterozygote for two mutations involving CDH23, with one allele typically associated with DFNB12 (missense mutation), and the other with USH1D (splice-site mutation). This is the first report of a sector RP phenotype in a patient with a DFNB12 allele and an USH1D allele.
Our patient is a 34-year-old, white female who was referred for evaluation of retinitis pigmentosa. The patient had a history of bilateral hearing loss diagnosed in preschool that required hearing aids. Her speech, motor development, and vestibular function were normal. Her family history was negative for similar symptoms, including hearing loss or significant visual abnormalities. On exam, the patient's visual acuity was 20/20 in the right eye and 20/25 in the left eye. Slit lamp exam, tonometry, and ocular motility were normal. Fundus exam showed bone spicule pigmentary changes in the inferior periphery of both eyes, but was negative for optic disc pallor and vascular attenuation (Figure 1). Humphrey visual field testing showed superior visual field defects bilaterally (Figure 2). Full-field electroretinogram (ERG) demonstrated normal A-wave and B-wave amplitudes and normal peak implicit times with normal trough to peak amplitudes. Optical coherence tomography (OCT) imaging showed normal foveal profile in both eyes without macular edema (Figure 2).
Color montage of the right (A) and left (B) eyes showing bone spicule pigmentary changes in the inferior periphery. The right eye is slightly worse than the left. Spectral-domain optical coherence tomography horizontal line scans through the fovea of the right (C) and the left (D) eyes showing normal foveal profiles bilaterally.
Humphrey visual field tests of the right and left eyes show superior visual field defects.
Based on her hearing loss and pigmentary changes to her retina, testing for genes associated with Usher syndrome was performed. Two abnormalities in CDH23 were identified, including a missense mutation (c.8530C > A; p.Pro2844Thr) and a splice-site mutation (c.5820 + 5G > A) (Table). The missense mutation is predicted to be significant (probably damaging) based on Polyphen-2 analysis, and the splice-site mutation is predicted to affect splicing based on analysis from the Berkeley Drosophila Genome Project. Parental testing showed that the Pro2844Thr missense mutation was inherited from her father and the c.5820 + 5 G > A splice-site mutation was inherited from her mother, demonstrating that she is a compound heterozygote for these findings (ie, her mutations are in trans). A heterozygous, maternally-inherited variant in USH1G (c.1258C > G; p.Leu420Val) was also found. Our patient only has one abnormality identified in USH1G, making her at least a carrier for this mutation. However, the clinical significance of being a carrier for this USH1G mutation is unclear at this time.
Mutations Detected in our Patient
Usher syndrome is the most common syndromic pigmentary retinopathy and commonly presents with typical diffuse RP characterized by abnormal retinal pigmentation and peripheral bone spicules.2,3 There are multiple types of Usher syndrome, with several genetic loci responsible for the varying phenotypes. We focus here on USH1D, which is caused by homozygous or compound heterozygous mutations of CDH23. There have been three previous reports of sector RP in patients with Usher syndrome, but none of these are known to be associated with mutations of CDH23. A study of 157 individuals with a clinical diagnosis of Usher syndrome showed that 90% had diffuse RP and only one had sector RP.4 An Usher syndrome type 1 patient with a secondary retinal vasoproliferative tumor was reported to have sector RP, but the genotype was not documented.5 Saihan et al. reported two siblings who were compound heterozygous for a splice-site and missense mutation in USH1C causing sector RP, sensorineural hearing loss, and vestibular involvement.6 Therefore, we report the first case of sector RP involving mutations of CDH23.
The product of CDH23, cadherin-23, is a trans-membrane protein complex that functions in both the cochlea and the retina, which explains the auditory and visual syndrome observed in patients with mutations in this gene.2 Our patient's presentation appears to follow this phenotypic heterogeneity and presumed genotype-phenotype relationship associated with mutations of CDH23.1 Missense mutations in CDH23 have been shown to cause nonsyndromic DFNB12 deafness or USH1D with very mild RP, whereas frameshift, splice-site, nonsense, and some missense mutations result in USH1D with typical Usher syndrome findings.1,2 This could be explained by the fact that missense mutations may allow enough production of functional cadherin-23 to preserve vestibular and retinal function, but not hearing, thereby resulting in hearing loss (DFNB12).1–3 Our patient was found to have both a missense and a splice-site mutation of CDH23. Compound heterozygotes for a missense and a splice-site mutation of CDH23 can present with a variety of retinal phenotypes.7 Shultz et al. showed that if a DFNB12 allele is located in trans to an USH1D allele (ie, compound heterozygosity), the DFNB12 phenotype appears to be more dominant, preserving both retinal and vestibular function.3 This supports a better visual prognosis for our patient but does not explain the sector RP phenotype. In addition, the spectrum of RP phenotypes associated with CDH23 mutations can differ in age of onset and rate of progression, making it difficult to predict the disease course. For this reason, we cannot rule out the possibility that her observed sector RP may eventually progress into diffuse RP.8 However, the normal electroretinogram readings in both eyes may make it less likely that this is a progressive and diffuse RP pattern.
In conclusion, we report the first patient with sector RP and congenital hearing loss in the absence of vestibular symptoms, who has two novel compound heterozygous CDH23 mutations. We suspect that our patient falls within the spectrum of phenotypes associated with CDH23 mutations (ie, between DFNB12 and USH1D). The milder nature of the visual symptoms coincides with what was previously discovered in patients who are compound heterozygous for a DFNB12 and USH1D allele.3 The sector RP may be the result of a dominant hypofunctioning CDH23 allele (as seen in DFNB12), or a new presentation attributable to the complexity of mutations within this gene. Overall, the patient's genotype appears to confer better visual prognosis compared to most patients with USH1. Functional studies of our patient's particular CDH23 mutations may further elucidate the role of these novel mutations in disease phenotype and lead to targeted ophthalmic treatments.
- Astuto LM, Bork JM, Weston MD, et al. CDH23 mutation and phenotype heterogeneity: A profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet. 2002;71(2):262–275. doi:10.1086/341558 [CrossRef]
- Millán JM, Aller E, Jaijo T, Blanco-Kelly F, Gimenez-Pardo A, Ayuso C. An update on the genetics of usher syndrome. J Ophthalmol. 2011;2011:417217. doi:10.1155/2011/417217 [CrossRef]
- Bocquet B, Lacroux A, Surget M-O, et al. Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management. Ophthalmic Epidemiol. 2013;20(1):13–25. doi:10.3109/09286586.2012.737890 [CrossRef]
- Haim M, Rosenberg T. Retinitis pigmentosa and allied disorders in Denmark. Acta Opthalmologica. 1993;71(5):597–605. doi:10.1111/j.1755-3768.1993.tb04648.x [CrossRef]
- Osman SA, Aylin Y, Gul A, Celikel H. Photodynamic treatment of a secondary vasoproliferative tumour associated with sector retinitis pigmentosa and Usher syndrome type I. Clin Exp Ophthalmol. 2007;35(2):191–193. doi:10.1111/j.1442-9071.2007.01440.x [CrossRef]
- Saihan Z, Stabej PLQ, Robson AG, et al. Mutations in the USH1C gene associated with sector retinitis pigmentosa and hearing loss. Retina. 2011;31(8):1708–1716. doi:10.1097/IAE.0b013e31820d3fd1 [CrossRef]
- Bolz H, von Brederlow B, Ramírez a, et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet. 2001;27(1):108–112. doi:10.1038/83667 [CrossRef]
- Ramon E, Cordomi A, Aguila M, et al. Differential light-induced responses in sectorial inherited retinal degeneration. J Biol Chem. 2014;289(52):35918–35928. doi:10.1074/jbc.M114.609958 [CrossRef]
Mutations Detected in our Patient
|Mutation Type||Mutation||Inheritance Pattern|
|CDH23 missense mutation||c.8530C>A, p.Pro2844Thr||Paternal|
|CDH23 splice-site mutation||c.5820+5G>A||Maternal|
|USH1G variation||c.1258C>G, p.Leu420Val||Maternal|