title: Association of Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy.
abstract: 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.
  
  
  
  To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its retinal manifestations and other associated features.
  
  
  
  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.
  
  
  
  Detailed clinical phenotypes as well as genetic and biochemical 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.
  
  
  
  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.
authors.affiliation: Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, England2Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, England.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Taylor
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, England.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, England.
authors.forename: James A
authors.initials: JA
authors.lastname: Poulter
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, England 5Department of Ophthalmology, St. James's University Hospital, Leeds, England.
authors.forename: Kamron N
authors.initials: KN
authors.lastname: Khan
authors.affiliation: Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, Central Manchester Foundation Trust, Manchester, England.
authors.forename: Jiten
authors.initials: J
authors.lastname: Morarji
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, England 7Moorfields Eye Hospital, London, England.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: UCL Genetics Institute, University College London, London, England.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pontikos
authors.affiliation: Genomics England, Queen Mary University of London, London, England.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rueda Martin
authors.affiliation: Genomics England, Queen Mary University of London, London, England.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Smith
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, England.
authors.forename: Manir
authors.initials: M
authors.lastname: Ali
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, England.
authors.forename: Carmel
authors.initials: C
authors.lastname: Toomes
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, England 5Department of Ophthalmology, St. James's University Hospital, Leeds, England.
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.affiliation: Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, England2Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, England.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Metabolic Unit, Great Ormond Street Hospital, London, England11Institute for Child Health, University College London, London, England.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grunewald
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, England 7Moorfields Eye Hospital, London, England.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, England 12Department of Ophthalmology, University of California, San Francisco, Medical School, San Francisco.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, England 7Moorfields Eye Hospital, London, England.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, England.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, England 7Moorfields Eye Hospital, London, England.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: Genomic Medicine, Division of Evolution and Genomic Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, England2Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Saint Mary's Hospital, Manchester, England.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000293:Adolescent; D018981:Congenital Disorders of Glycosylation / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D059472:Exome / Q000235:genetics; D005260:Female; D005451:Fluorescein Angiography; D016678:Genome / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014786:Vision Disorders / Q000175:diagnosis / Q000235:genetics*; D014792:Visual Acuity / Q000502:physiology; D058609:Visual Field Tests; D014794:Visual Fields; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548469:SRD5A3 protein, human