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Using the single-cell transcriptome to facilitate molecular diagnosis of retinal dystrophy -- a case report

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction
Inherited retinal dystrophies are a highly heterogeneous group of diseases, especially when locus heterogeneity and mode of inheritance are considered. Currently, there are more than 100 genes for this group of diseases.

Case Presentation
A man in his 40s first visited our eye clinic in June 2023 and complained about reduced central vision in his left eye. This summer, vision impairment was also noticed in his right eye. Detailed ophthalmology examinations revealed abnormal ERG in cone cells, while rod cells remained unaffected. OCT revealed the defect is limited to photoreceptor cells at the macula. The RPE cells were unaffected based on fundus autofluorescence.

Diagnostic Workup
Owing to the lack of family history for his eye conditions, WES was filtered under the recessive mode of inheritance and a virtue panel of genes known to cause retinal dystrophy. The top-ranked genes were RP1L1, CNGA1, AHI1, ALMS1, and ADH7 with VUS variants. We utilized single-cell RNA sequencing data from adult humans and found that only RP1L1 revealed a high expression level in cone cells and much lower levels in rod and RPE cells. On the other hand, the CNGA1 and ALMS1 expression levels are much higher in rod cells than in cone cells. The expression level of AHI1 is similar between cone and rod cells. There is little expression of ADH7 among all the retinal cells annotated.

Treatment and Management
The patient’s care focused on avoiding unnecessary invasive procedures and experimental treatments, sometimes considered when a diagnosis is uncertain. Early in the diagnostic process, the patient underwent MRI and cerebrospinal fluid (CSF) testing at the other hospital to rule out other potential neurological causes. With the confirmation of occult macular dystrophy (OMD) attributed to RP1L1 mutations, we were able to halt these additional evaluations and avoid potentially unwarranted treatments, such as systemic steroids and intravitreal injections, which have limited utility in OMD and could pose an unnecessary risk to the patient.

Outcome and Follow-Up
Following the initial onset, the patient experienced rapid progression of vision impairment, with each eye affected approximately one year apart. Follow-up OCT scans showed subtle macular changes initially, becoming more pronounced as the disease progressed. Although no cure for OMD exists, the genetic diagnosis allowed for more targeted management, focusing on regular ophthalmic follow-ups to monitor disease progression and adapt visual support measures. No further invasive tests or therapeutic interventions were pursued, which was consistent with best practices for OMD.

Discussion
This case underscores the utility of single-cell transcriptomic analysis in confirming RP1L1 as the causative gene, which was critical given the atypical presentation and initially unclear genetic diagnosis. OMD often poses diagnostic challenges due to its subtle early presentation on OCT and its rapid progression once symptoms appear. The disease's course, involving delayed onset in the second eye and fast progression, aligns with findings in some OMD cases but highlights the variability in clinical presentations. By pinpointing RP1L1 as the underlying gene, this case illustrates how precise genetic dissection can guide clinical decisions, helping to avoid unnecessary, invasive tests and treatments. These findings contribute to the literature on OMD and demonstrate the value of integrating advanced molecular diagnostics to refine patient care and improve diagnostic accuracy for rare retinal dystrophies.

Conclusion
The retina is composed of several cell types. Only one to a few may be the primary defect in an inherited retinal dystrophy. In this case, the macula cone photoreceptor cell is the cell type that revealed an early pathological change in ERG. Using gene expression levels from the single-cell transcriptome, PR1L1 is the only gene with significant expression in the cone cells and a much lower level in rod and RPE cells and consistent with the clinical presentation.

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