July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Mutations in WDR34 is a rare cause of non-syndromic autosomal recessive rod-cone dystrophy
Author Affiliations & Notes
  • Isabelle S Audo
    Department of Genetics, Inst de la Vision/INSERM/UPMC/CNRS/CHNO, Paris, France
    DHU Sight Restore, INSERM-DHOS CIC1423, CHNO des Quinze-Vingts, Paris, France
  • Maria Solaguren-Beascoa
    Department of Genetics, Inst de la Vision/INSERM/UPMC/CNRS/CHNO, Paris, France
  • Kinga Bujakowska
    Department of Ophthalmology, Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Cécile Méjécase
    Department of Genetics, Inst de la Vision/INSERM/UPMC/CNRS/CHNO, Paris, France
  • Lisa Emmengger
    Department of Genetics, Inst de la Vision/INSERM/UPMC/CNRS/CHNO, Paris, France
  • Saddek Mohand-Said
    DHU Sight Restore, INSERM-DHOS CIC1423, CHNO des Quinze-Vingts, Paris, France
  • Thierry D Leveillard
    Department of Genetics, Inst de la Vision/INSERM/UPMC/CNRS/CHNO, Paris, France
  • Eric A Pierce
    Department of Ophthalmology, Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Helene Dollfus
    Centre de Référence pour les Affections Rares en Génétique Ophtalmologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  • Jose Alain Sahel
    Department of Genetics, Inst de la Vision/INSERM/UPMC/CNRS/CHNO, Paris, France
    DHU Sight Restore, INSERM-DHOS CIC1423, CHNO des Quinze-Vingts, Paris, France
  • Shomi Bhattacharya
    UCL-Institute of Ophthalmology, United Kingdom
  • Christina Zeitz
    Department of Genetics, Inst de la Vision/INSERM/UPMC/CNRS/CHNO, Paris, France
  • Footnotes
    Commercial Relationships   Isabelle Audo, None; Maria Solaguren-Beascoa, None; Kinga Bujakowska, None; Cécile Méjécase, None; Lisa Emmengger, None; Saddek Mohand-Said, None; Thierry Leveillard, None; Eric Pierce, None; Helene Dollfus, None; Jose Sahel, None; Shomi Bhattacharya, None; Christina Zeitz, None
  • Footnotes
    Support  The project was supported by Retina France, Foundation Voir et Entendre, Foundation Fighting Blindness (FFB Grant # CD-CL-0808-0466-CHNO and the CIC503 recognized as an FFB center, FFB Grant # CC-CL-0912-0600-INSERM01 and GE-0912-0601-INSERM), Ville de Paris and Région Ile de France and by the French State program "Investissements d'Avenir" managed by the Agence Nationale de la Recherche [LIFESENSES: ANR-10-LABX-65], National Eye Institute s of Health (USA) (EAP- R01EY012910, EAP/KMB- R01EY026904, Genomics Core -P30EY014104)KB, EAP NIH, Grant No: 1R01EY020902 - 01A1), European Reintegration Grant PERG04-GA-2008-231125, Prix Dalloz (CZ), doctoral funding from the Ministère de l’Enseignement Supérieur et de la Recherche and Fondation de France-Berthe Fouassier, Europe exchange 2018 Erasmus.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 381. doi:https://doi.org/
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      Isabelle S Audo, Maria Solaguren-Beascoa, Kinga Bujakowska, Cécile Méjécase, Lisa Emmengger, Saddek Mohand-Said, Thierry D Leveillard, Eric A Pierce, Helene Dollfus, Jose Alain Sahel, Shomi Bhattacharya, Christina Zeitz; Mutations in WDR34 is a rare cause of non-syndromic autosomal recessive rod-cone dystrophy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):381. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To identify the underlying gene defect in a patient with non-syndromic rod-cone dystrophy (RCD).

Methods : A 27-year old patient, of Portuguese descent and consanguineous union, with a presumed diagnosis of sporadic RCD was included in the study after informed consent. The DNA of the index patient was initially investigated applying microarray analysis, and direct Sanger sequencing of EYS and PCARE. Homozygosity mapping using a 700K genome-wide SNP microarray (Illumina HumanOmniExpress) was subsequently performed followed by Sanger sequencing of exonic regions known to be mutated in retinal dystrophies within homozygous regions. Whole exome sequencing (WES) was subsequently applied to the DNA of the index patient and his unaffected parents followed by segregation analysis in all available family members using Sanger sequencing. Further Sanger sequencing of the 9 exons and flanking regions of WDR34 (Refseq NM_052844.3) was performed on 1285 presumed autosomal recessive and sporadic cases with non syndromic RCD. The expression of WDR34 was investigated in transcriptomic databases and by RT-PCR and in situ hybridization experiments.

Results : Ophthalmic examination confirmed the diagnosis of RCD with macular involvement in the patient. There was no evidence of additional systemic abnormalities excluding a syndromic involvement. Microarray analysis and direct targeted sequencing did not identify disease causing variant. Homozygosity mapping identified 21homozygous regions ranging from 9kb to 77.7Mb. Subsequent whole exome sequencing identified a total 69552 unique variants with a global coverage of 95%. After stringent filtering for rare variants with predicted high functional impact, two variants were retained including the c.1241A>G change leading to p.(Asp414Gly) substitution in WDR34 which lies in a large homozygous region and co-segregated with the phenotype in the family. Mutation screening of additional 1285 presumed autosomal recessive non-syndromic RCD cases did not reveal any other likely pathogenic changes in WDR34.

Conclusions : This is the first report of a homozygous variant in WDR34 in a retina-restricted disease. Further functional studies will help better define phenotype/genotype correlations associated with WDR34 mutations leading either to severe syndromic ciliopathies or to non syndromic RCD, the latter appearing to be a rare occurrence.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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