The overall goal of this project, co-funded by the Foundation Fighting Blindness and the USHER 1F Collaborative is to characterize the natural history of disease progression in patients with PCDH15 mutations in order to accelerate the development of outcome measures for clinical trials.

This natural history study of patients with PCDH15 disease-causing variants will accelerate the development of outcome measures for clinical trials. Sensitive, reliable outcome measures of retinal degeneration will greatly facilitate development of treatments for retinitis pigmentosa due to PCDH15 disease-causing variants. Together these approaches are expected to have an impact on understanding PCDH15 related retinal degeneration, developing experimental treatment protocols, and assessing their effectiveness.

The goals and expected impact of this natural history study are to:

1. Describe the natural history of retinal degeneration in patients with biallelic disease-causing variants in the PCDH15 gene
2. Contribute to the identification of sensitive structural and functional outcome measures to use for future multicenter clinical trials in PCDH15 related retinal degeneration
3. Contribute to the identification of populations for future clinical trials of investigative treatments for PCDH15 related retinal degeneration

Study Objectives

The primary objectives of the natural history study are to:

1. Characterize the natural history of retinal degeneration associated with biallelic pathogenic mutations in the PCDH15gene over 4 years, as measured using functional, structural, and patient-reported outcome measures
2. Explore whether structural outcome measures can be validated as surrogates for functional outcomes in individuals with biallelic pathogenic mutations in the PCDH15 gene
3. Explore possible risk factors (genotype, phenotype, environmental, and comorbidities) for progression of the outcome measures at 4 years in individuals with biallelic pathogenic mutations in the PCDH15 gene
4. Explore variability and symmetry of left and right eye outcomes over 4 years in individuals with biallelic pathogenic mutations in the PCDH15 gene

Inclusion Criteria:

Participants must meet all the following inclusion criteria at the Screening Visit in order to be eligible to enroll into the genetic screening phase.

1. Willing to participate in the study and able to communicate consent during the consent process

2. Ability to return for all study visits over 48 months

3. Age ≥ 8 years

4. Not planning to enroll in an experimental clinical trial for the treatment of PCDH15 for the duration of this study

5. Must meet one of the Genetic Screening Criteria, defined below:

   • Screening Group A: At least 2 disease-causing variants in the PCDH15 gene which are homozygous or heterozygous in trans, based on a report from a clinically certified lab (or a report from a research lab that has been pre- approved by the Genetics Committee)
   • Screening Group B: Only 1 disease-causing variant in the PCDH15 gene, based on a report from a clinically certified lab (or a report from a research lab which has been pre-approved by the Genetics Committee)
   • Screening Group C: At least 2 disease-causing variants in the PCDH15 gene which are unknown phase, based on a report from a clinically certified lab (or a report from a research lab which has been pre-approved by the Genetics Committee)

Note pertaining to all Screening Groups: if a participant has a variant(s) of unknown significance, he/she would still qualify if there is at least 1 disease-causing variant(s) on the PCDH15 gene. The Genetics Committee will review unique cases where segregation analysis is not feasible to determine eligibility.

Ocular Inclusion Criteria

Both eyes must meet all the following at the Screening Visit for a participant to be eligible to enroll into the genetic screening phase.

1. Clinical diagnosis of retinal dystrophy
2. Clear ocular media and adequate pupil dilation to permit good quality photographic imaging

Exclusion Criteria:

Participants must not meet any of the following exclusion criteria at the Screening Visit in order to be eligible to enroll into the genetic screening phase.

1. Mutations in genes that cause autosomal dominant retinitis pigmentosa (ADRP), X-linked retinitis pigmentosa (RP), or presence of biallelic mutations in autosomal recessive RP/retinal dystrophy genes other than PCDH15
2. Expected to enter experimental treatment trial at any time during this study
3. History of more than 1 year of cumulative treatment, at any time, with an agent associated with pigmentary retinopathy (including hydroxychloroquine, chloroquine, thioridazine, and deferoxamine)

Note: Pregnant women are not being specifically excluded from participation.

Ocular Exclusion Criteria

If either eye has any of the following at the Screening Visit, the participant is not eligible to enroll into the genetic screening phase.

1. Current vitreous hemorrhage

2. Current or any history of tractional or rhegmatogenous retinal detachment

3. Current or any history of (e.g., prior to cataract or refractive surgery) spherical equivalent of the refractive error worse than -8 Diopters of myopia

4. History of intraocular surgery (e.g., cataract surgery, vitrectomy, penetrating keratoplasty, or LASIK) within the last 3 months

5. Current or any history of confirmed diagnosis of glaucoma (e.g., based on glaucomatous VF changes or nerve changes, or history of glaucoma filtering surgery)

6. Current or any history of retinal vascular occlusion or proliferative diabetic retinopathy

7. History or current evidence of ocular disease that, in the opinion of the investigator, may confound assessment of visual function

8. History or evidence of active treatment for retinitis pigmentosa that could affect the progression of retinal degeneration, including:

   1. Any use of ocular stem cell or gene therapy
   2. Any treatment with ocriplasmin
   3. Treatment with an ophthalmic oligonucleotide within the last 9 months (last treatment date is less than 9 months prior to Screening Visit date)
   4. Treatment with any other product within five times the expected half-life of the product (time from last treatment date to Screening Visit date is at least 5 times the half-life of the given product)
   5. Treatment with Ozurdex (dexamethasone), Iluvien or Yutiq (fluocinolone acetonide) intravitreal implant

Study participants will be recruited from approximately 10 clinical sites worldwide. All eligible participants will be included without regard to gender, race, or ethnicity. Potential eligibility will be assessed during a routine examination by an investigator prior to obtaining informed consent, as part of usual care, through referrals from other providers or self-referral.

A de-identified database is placed in the public domain on the FFB/Jaeb public website after the completion of each protocol and publication of the manuscript.

After manuscript is published

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