Association of Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy

Importance: Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation. Its retinal phenotype is not well described but could be important for disease recognition because it appears to be a consistent primary presenting feature. Objective: To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its retinal manifestations and other associated features. Design, Setting and Participants: Seven affected individuals from 4 unrelated families with early-onset retinal dystrophy as a primary manifestation underwent comprehensive ophthalmic assessment, including retinal imaging and electrodiagnostic testing. Developmental and systemic findings were also recorded. Molecular genetic approaches, including targeted next-generation sequencing, autozygosity mapping, and apex microarray, were tried to reach a diagnosis; all participants were mutation negative. Whole-exome sequencing or whole-genome sequencing was used to identify the causative variant. Biochemical profiling was conducted to confirm a CDG type I defect. Patient phenotype data were collected over the course of ophthalmic follow-up, spanning a period of 20 years, beginning March 20, 1997, through September 15, 2016. Main Outcomes and Measures: Detailed clinical phenotypes as well as genetic and biochemical results. Results: The cohort consisted of 7 participants (5 females and 2 males) whose mean (SD) age at the most recent examination was 17.1 (3.9) years and who were all of South Asian ethnicity. Whole-exome sequencing and whole-genome sequencing identified the same homozygous SRD5A3 c.57G>A, p.(Trp19Ter) variant as the underlying cause of early-onset retinal dystrophy in each family. Detailed ocular phenotyping identified early-onset (aged ≤3 years) visual loss (mean [SD] best-corrected visual acuity, +0.95 [0.34] logMAR [20/180 Snellen]), childhood-onset nyctalopia, myopia (mean [SD] refractive error, -6.71 [-4.22]), and nystagmus. Six of the 7 patients had learning difficulties and psychomotor delay. Fundus autofluorescence imaging and optical coherence tomographic scans were abnormal in all patients, and electrodiagnostic testing revealed rod and cone dysfunction in the 5 patients tested. Conclusions and Relevance: Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. SRD5A3 and other glycosylation disorder genes should be considered as a cause of retinal dystrophy even when systemic features are mild. Further delineation of SRD5A3-associated eye phenotypes can help inform genetic counseling for prognostic estimation of visual loss and disease progression

Late-onset autosomal dominant macular degeneration caused by deletion of the CRX gene

Purpose To characterise the phenotype observed in a case series with macular disease and determine the cause. Design Multi-centre case series. Participants Six families (seven patients) with sporadic or multiplex macular disease with onset at 36-78 years, and one patient with age-related macular degeneration. Methods Patients underwent ophthalmic examination, exome, genome or targeted sequencing, and/or PCR amplification of the breakpoint followed by cloning and Sanger sequencing or direct Sanger sequencing. Main Outcome Measures Clinical phenotypes, genomic findings and a hypothesis explaining the mechanism underlying disease in these patients. Results All eight cases carried the same deletion encompassing the genes TPRX1, CRX and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13,096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridisation. Microsatellite genotypes showed that these seven families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. Conclusions Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease