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Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.

  • Weisschuh N Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
  • Sturm M Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
  • Baumann B Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
  • Audo I Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France.
  • Ayuso C Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD UAM), Madrid, Spain.
  • Bocquet B Centre National de Référence «Maladies Sensorielles Génétiques», Service Ophtalmologie, Hôpital Gui de Chauliac, CHRU de Montpellier, Montpellier, France.
  • Branham K Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan.
  • Brooks BP National Eye Institute, National Institutes of Health, Bethesda, Maryland.
  • Catalá-Mora J Ophthalmology, Hospital Sant Joan de Deu, Barcelona, Spain.
  • Giorda R Molecular Biology Lab, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Italy.
  • Heckenlively JR Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan.
  • Hufnagel RB National Eye Institute, National Institutes of Health, Bethesda, Maryland.
  • Jacobson SG Department of Ophthalmology, Perelman School of Medicine, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Kellner U Rare Retinal Disease Center, Augenzentrum Siegburg, MVZ ADTC Siegburg GmbH, Siegburg, Germany.
  • Kitsiou-Tzeli S Department of Medical Genetics, National & Kapodistrian University of Athens, Athens, Greece.
  • Matet A Department of Ophthalmology, Jules-Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.
  • Martorell Sampol L Laboratorio de Genética Molecular, Hospital Sant Joan de Deu, Barcelona, Spain.
  • Meunier I Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
  • Rudolph G Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany.
  • Sharon D Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
  • Stingl K University Eye Hospital, Center for Ophthalmology, University of Tübingen, Tübingen, Germany.
  • Streubel B Department of Pathology, Medical University of Vienna, Vienna, Austria.
  • Varsányi B Department of Ophthalmology, Semmelweis University, Budapest, Hungary.
  • Wissinger B Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
  • Kohl S Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.
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  • 2019-09-24
Published in:
  • Human mutation. - 2020
CNGB3
achromatopsia
deep intronic variant
pseudoexon
splicing defect
English Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.
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  • English
Open access status
bronze
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https://sonar.ch/global/documents/268649
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