July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Mild deep-intronic ABCA4 variants explain genetically unsolved cases of very late-onset Stargardt disease
Author Affiliations & Notes
  • E.H. Henrike Runhart
    Ophthalmology, Radboud university medical center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Dyon Valkenburg
    Ophthalmology, Radboud university medical center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Stephanie Cornelis
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
    Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • Mubeen Khan
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
    Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • Riccardo Sangermano
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
    Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • Galuh D.N. Astuti
    Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • Silvia Albert
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
    Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • nathalie m bax
    Ophthalmology, Radboud university medical center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Jan-Willem R. Pott
    Ophthalmology, University Medical Center Groningen, Groningen, Netherlands
  • Joke B.G.M. Verheij
    Medical Genetics, University Medical Center Groningen, Groningen, Netherlands
  • Ellen A.W. Blokland
    Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • Frans P Cremers
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
    Human Genetics, Radboud university medical center, Nijmegen, Netherlands
  • L. Ingeborgh van den Born
    The Rotterdam Eye Hospital and the Rotterdam Ophthalmic Institute, Rotterdam, Netherlands
  • Carel C B Hoyng
    Ophthalmology, Radboud university medical center, Nijmegen, Netherlands
    Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, Netherlands
  • Footnotes
    Commercial Relationships   E.H. Runhart, None; Dyon Valkenburg, None; Stephanie Cornelis, None; Mubeen Khan, None; Riccardo Sangermano, None; Galuh Astuti, None; Silvia Albert, None; nathalie bax, None; Jan-Willem Pott, None; Joke Verheij, None; Ellen Blokland, None; Frans Cremers, None; L. van den Born, None; Carel Hoyng, None
  • Footnotes
    Support  Retina UK grant no. GR591; Fighting Blindness Ireland grant; FP7-PEOPLE-2012-ITN programme EyeTN, Foundation Fighting Blindness USA grant PPA-0517-0717-RAD
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1338. doi:
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      E.H. Henrike Runhart, Dyon Valkenburg, Stephanie Cornelis, Mubeen Khan, Riccardo Sangermano, Galuh D.N. Astuti, Silvia Albert, nathalie m bax, Jan-Willem R. Pott, Joke B.G.M. Verheij, Ellen A.W. Blokland, Frans P Cremers, L. Ingeborgh van den Born, Carel C B Hoyng; Mild deep-intronic ABCA4 variants explain genetically unsolved cases of very late-onset Stargardt disease. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1338.

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

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Abstract

Purpose : To describe the phenotypic features, to assess the penetrance, and to investigate the effect on splicing in patient-derived photoreceptor precursor cells (PPCs) of two Stargardt disease (STGD1)-associated intronic ABCA4 variants that were found to show a partial splice defect in vitro.

Methods : Segregation-analysis was performed in 13/15 families carrying c.769-784C>T or c.4253+43G>A. Retrospective ophthalmologic data were assessed of all 15 probands and their affected siblings. The penetrances of c.769-784C>T and c.4253+43G>A were calculated using ABCA4 allele frequency data of one European and two Dutch population databases. Reverse-transcription PCR was performed on mRNA isolated from patient-derived PPCs carrying these variants in a heterozygous manner.

Results : Subjects who harbor c.4253+43G>A or c.769-784C>T mostly manifest late-onset STGD1, with a median age of onset of 52.0 and 54.5 years, respectively. A slowly progressive decline in visual acuity was observed in the majority of the patients, due to the gradual progression of macular atrophy in a foveal sparing pattern. We calculated the penetrances of c.4253+43G>A and c.769-784C>T, in trans with a severe variant, to be reduced to 43.1% and 20.5%, respectively, based on the allele frequencies of these intronic variants in the Dutch population. In patient-derived PPCs, variant c.769-784C>T resulted in partial pseudo-exon insertion, and variant c.4253+43G>A in partial deletion of exon 28.

Conclusions : ABCA4 variants c.4253+43G>A and c.769-784C>T were associated with late-onset, slowly progressive, STGD1 due to mild splice defects. Both variants were calculated to be reduced penetrant when not taking into account the effect of known, and yet unidentified, factors in cis. We hypothesize that several genetic or non-genetic factors influence the expression and the penetrance of these mild variants.

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

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