Aims We aimed to accurately diagnose several retinitis pigmentosa (RP) patients with complex ocular phenotypes by combining massive sequencing genetic diagnosis and powerful clinical imaging techniques.
Methods Whole-exome sequencing (WES) of selected patients from two RP families was undertaken. The variants identified were validated by Sanger sequencing and cosegregation analysis. Accurate clinical re-evaluation was performed using electrophysiological and visual field records as well as non-invasive imaging techniques, such as swept-source optical coherence tomography and fundus autofluorescence.
Results The WES results highlighted one novel and one reported causative mutations in the X-linked choroideremia gene (CHM), which challenged the initial RP diagnosis. Subsequent clinical re-evaluation confirmed the choroideremia diagnosis. Carrier females showed different degrees of affectation, even between twin sisters, probably due to lyonization. A severe multi-Mendelian phenotype was associated with coincidental dominant pathogenic mutations in two additional genes: PAX6 and PDE6B.
Conclusions Genetic diagnosis via massive sequencing is instrumental in identifying causative mutations in retinal dystrophies and additional genetic variants with an impact on the phenotype. Multi-Mendelian phenotypes previously ascribed to rare syndromes can thus be dissected and molecularly diagnosed. Overall, the combination of powerful genetic diagnosis and clinical non-invasive imaging techniques enables efficient management of patients and their prioritisation for gene-specific therapies.
- diagnostic tests/investigation
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RPC-M and RG-D contributed equally.
Contributors Conceptualisation: MdC-M, RT, RPC-M and RG-D. Data curation, investigation, methodology: MdC-M, RT and RPC-M. Formal analysis: MdC-M, RPC-M and RG-D. Funding acquisition and project administration: RG-D. Resources: RPC-M and RG-D. Software: MdC-M and RT. Supervision: GM and RG-D. Validation and visualisation: MdC-M and RPC-M. Writing, original draft: GM and RG-D. Writing, review and editing: all authors.
Funding The study was supported by the 2013 CNAG Call '300 EXOMES TO ELUCIDATE RARE DISEASES'. This activity was sponsored by grants SAF2013-49069-C2-R-1 (Ministerio de Economía y Competitividad/FEDER), 2014SGR-0932 (Generalitat de Catalunya), La Marató TV3 (Project Marató 201417-30-31-32) to GM and RGD. RT is funded by PT13/0001/0044 (ISCIII Ministerio de Economía y Competitividad).
Competing interests None declared.
Patient consent Obtained.
Ethics approval All the research procedures were approved by the Bioethics Committee of the Universitat de Barcelona (Barcelona, Spain).
Provenance and peer review Not commissioned; externally peer reviewed.