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Novel mutation in the choroideremia gene and multi-Mendelian phenotypes in Spanish families
  1. Marta de Castro-Miró1,2,3,
  2. Raul Tonda4,5,
  3. Gemma Marfany1,2,3,
  4. Ricardo P Casaroli-Marano6,
  5. Roser Gonzàlez-Duarte1,2,3
  1. 1 Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
  2. 2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
  3. 3 Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain
  4. 4 CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
  5. 5 Universitat Pompeu Fabra (UPF), Barcelona, Spain
  6. 6 Department of Surgery, School of Medicine and Hospital Clínic de Barcelona (IDIBAPS), University of Barcelona, Barcelona, Spain
  1. Correspondence to Dr Roser Gonzàlez-Duarte, Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Barcelona 08028, Spain; rgonzalez{at}


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.

  • choroid
  • diagnostic tests/investigation
  • Iris
  • imaging
  • dystrophy

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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.

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