Background Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.
Methods Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role.
Results Exome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.
Conclusion This study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.
- sequence analysis
- eye diseases
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Contributors GO, MC, C-MD, AA-F, BB, AS performed sequencing analyses. GO, DI, IC performed the in vivo studies. SKV, PIS, GLM, HN, AR, GCB, CLH, JK, XZ, IM collected clinical cases and performed clinical examinations of patients. GM, SR, IC, SB, AM, CA, CBH designed the study. GM, IM, SR, PIS, SKV, C-MD drafted the manuscript. All authors revised the manuscript.
Funding The work of GM is supported by SOS Rétinite Pigmentaire foundation (#20142016/1051). The work of GO was funded by the associations Valentin Haüy/Retina France fellowship (#RAK18006FFA). This project was funded by the French Foundation for Rare Disease (#201607), by grants from the Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Health, including CIBERER (06/07/0036), IIS-FJD Biobank (PT13/0010/0012) and FIS (PI16/00425); and from the regional government of Madrid, RAREGenomics-CM (CAM, B2017/BMD-3721). MC is supported by the Miguel Servet Program (CP12/03256) from ISCIII. This research was supported by the Laboratory of Excellence GENMED-Medical Genomics (ANR-10-LABX-0013) managed by the National Research Agency (ANR) part of the Investment for the Future programme. IFB acknowledges funding by the call “Infrastructures in Biology and Health” in the framework of the French “Investments for the Future” (ANR-11-INBS-0013) initiative, and EU H2020 projects CYCLONE (644925), EXCELERATE (676559) and EGI-Engage (654142). IFB is the French ELIXIR node. The work of SR is supported by the Foundation Fighting Blindness USA Project Program Award (PPA-0517-0717-RAD), the Rotterdamse Stichting Blindenbelangen, the Stichting Blindenhulp, the Stichting tot Verbetering van het Lot der Blinden and the Stichting Blinden- Penning.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study (# 2008-A01238-47) received authorisation from the Sud Méditerranée IV ethical board committee (# 08 10 05 from 04/11/2008) and was approved by the French regulation agency for medication (AFSSAPS # B81319-70) and by the Research Ethics Committee of the Fundación Jimenez Diaz University Hospital. The investigators followed the tenets of the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information. Our exome sequencing data are in NCBI BioProject Sequence Read Archive (SRA) accession: PRJNA636189.
Author note Christain Hamel deceased in August 2017.
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