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Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants

  • Genetics
  • Published:
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Abstract

Purpose

The aim of this study was to determine the molecular genetic basis of an early-onset severe retinal dystrophy in three unrelated consecutive patients of Czech origin and to describe their ocular phenotype.

Methods

DNA samples from two probands were analyzed using a genotyping microarray (Asper) followed by either target analysis of 43 genes implicated in retinal disorders by next generation sequencing or whole-exome sequencing, respectively. The third proband underwent conventional Sanger sequencing of CRB1 based on her ocular findings.

Results

All three probands harboured a known disease-causing mutation c.2843G>A; p.(Cys948Tyr) in the CRB1 gene. One individual was homozygous for this mutation, while in the other two probands c.2308G>A; p.(Gly770Ser) and c.3121A>G; p.(Met1041Val) were also identified in the heterozygous state, respectively. Both variants were novel and evaluated by in silico analysis as pathogenic. A false-negative result was observed in one of the two samples examined by the genotyping microarray. Disease onset in all patients was before the age of 7 years. Hypermetropic refractive error, bilateral nummular retinal pigmentation, retinal thickening and cystoid spaces in the macula were observed in two probands, aged 6 and 7 years. The third proband, aged 28 years, had bone spicule-like pigmentary changes associated with increased retinal nerve fiber layer.

Conclusions

The first study reporting on the molecular genetic cause of non-syndromic early-onset severe retinal dystrophy in Czech patients identified one homozygous and two compound heterozygote probands with CRB1 mutations. Retina nerve fibre layer measurements should be considered an integral part of the clinical evaluation of retinal dystrophies. Detailed clinical examination and imaging can both direct molecular screening and help to confirm or refute disease causation of identified variants.

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Acknowledgment

The authors thank Kinga Bujakowska for providing CRB1 primers.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic

    Bohdan Kousal, Pavel Diblik & Petra Liskova

  2. Institute of Inherited Metabolic Disorders,General Teaching Hospital and First Faculty of Medicine, Charles University, Ke Karlovu 2, Praha 2, 128 08, Prague, Czech Republic

    Bohdan Kousal, Lubica Dudakova & Petra Liskova

  3. Department of Genetics, Faculty Hospital, Brno, Czech Republic

    Renata Gaillyova

  4. GENNET, Prague, Czech Republic

    Michaela Hejtmankova

  5. Moorfields Eye Hospital NHS Foundation Trust, London, UK

    Michel Michaelides

  6. UCL Institute of Ophthalmology, London, UK

    Michel Michaelides

Authors
  1. Bohdan Kousal
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  2. Lubica Dudakova
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  3. Renata Gaillyova
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  4. Michaela Hejtmankova
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  5. Pavel Diblik
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  6. Michel Michaelides
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  7. Petra Liskova
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Corresponding author

Correspondence to Petra Liskova.

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Funding

This work was supported by UNCE 204011 and PRVOUK-P24/LF1/3 programs of the Charles University in Prague and by Leontinka foundation. The sponsor had no role in the design or conduct of this research. BK is supported by SVV UK 260256/2016. MM is supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Foundation Fighting Blindness, the Special Trustees of Moorfields Eye Hospital and by an FFB Career Development Award. We thank The National Center for Medical Genomics (LM2015091) for bioinformatical support with next-generation sequencing data analysis and for providing ethnically matched population frequency data.

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Kousal, B., Dudakova, L., Gaillyova, R. et al. Phenotypic features of CRB1-associated early-onset severe retinal dystrophy and the different molecular approaches to identifying the disease-causing variants. Graefes Arch Clin Exp Ophthalmol 254, 1833–1839 (2016). https://doi.org/10.1007/s00417-016-3358-2

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  • DOI: https://doi.org/10.1007/s00417-016-3358-2

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