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Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides

(2019) GENETICS IN MEDICINE. 21(8). p.1751-1760
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Abstract
Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
Keywords
Genetics(clinical), ABCA4, antisense oligonucleotide, deep-intronic variant, missing heritability, Stargardt disease, IN-VITRO, MUTATIONS, GENE, REVEALS, POPULATION

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MLA
Sangermano, Riccardo et al. “Deep-intronic ABCA4 Variants Explain Missing Heritability in Stargardt Disease and Allow Correction of Splice Defects by Antisense Oligonucleotides.” GENETICS IN MEDICINE 21.8 (2019): 1751–1760. Print.
APA
Sangermano, R., Garanto, A., Khan, M., Runhart, E. H., Bauwens, M., Bax, N. M., van den Born, L. I., et al. (2019). Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides. GENETICS IN MEDICINE, 21(8), 1751–1760.
Chicago author-date
Sangermano, Riccardo, Alejandro Garanto, Mubeen Khan, Esmee H Runhart, Miriam Bauwens, Nathalie M Bax, L Ingeborgh van den Born, et al. 2019. “Deep-intronic ABCA4 Variants Explain Missing Heritability in Stargardt Disease and Allow Correction of Splice Defects by Antisense Oligonucleotides.” Genetics in Medicine 21 (8): 1751–1760.
Chicago author-date (all authors)
Sangermano, Riccardo, Alejandro Garanto, Mubeen Khan, Esmee H Runhart, Miriam Bauwens, Nathalie M Bax, L Ingeborgh van den Born, Muhammad Imran Khan, Stéphanie S Cornelis, Joke BGM Verheij, Jan-Willem R Pott, Alberta AHJ Thiadens, Caroline CW Klaver, Bernard Puech, Isabelle Meunier, Sarah Naessens, Gavin Arno, Ana Fakin, Keren J Carss, F Lucy Raymond, Andrew R Webster, Claire-Marie Dhaenens, Heidi Stöhr, Felix Grassmann, Bernhard HF Weber, Carel B Hoyng, Elfride De Baere, Silvia Albert, Rob WJ Collin, and Frans PM Cremers. 2019. “Deep-intronic ABCA4 Variants Explain Missing Heritability in Stargardt Disease and Allow Correction of Splice Defects by Antisense Oligonucleotides.” Genetics in Medicine 21 (8): 1751–1760.
Vancouver
1.
Sangermano R, Garanto A, Khan M, Runhart EH, Bauwens M, Bax NM, et al. Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides. GENETICS IN MEDICINE. 2019;21(8):1751–60.
IEEE
[1]
R. Sangermano et al., “Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides,” GENETICS IN MEDICINE, vol. 21, no. 8, pp. 1751–1760, 2019.
@article{8594153,
  abstract     = {Purpose: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability.
Methods: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.
Results: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.
Conclusion: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.},
  author       = {Sangermano, Riccardo and Garanto, Alejandro and Khan, Mubeen and Runhart, Esmee H and Bauwens, Miriam and Bax, Nathalie M and van den Born, L Ingeborgh and Khan, Muhammad Imran and Cornelis, Stéphanie S and Verheij, Joke BGM and Pott, Jan-Willem R and Thiadens, Alberta AHJ and Klaver, Caroline CW and Puech, Bernard and Meunier, Isabelle and Naessens, Sarah and Arno, Gavin and Fakin, Ana and Carss, Keren J and Raymond, F Lucy and Webster, Andrew R and Dhaenens, Claire-Marie and Stöhr, Heidi and Grassmann, Felix and Weber, Bernhard HF and Hoyng, Carel B and De Baere, Elfride and Albert, Silvia and Collin, Rob WJ and Cremers, Frans PM},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  keywords     = {Genetics(clinical),ABCA4,antisense oligonucleotide,deep-intronic variant,missing heritability,Stargardt disease,IN-VITRO,MUTATIONS,GENE,REVEALS,POPULATION},
  language     = {eng},
  number       = {8},
  pages        = {1751--1760},
  title        = {Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides},
  url          = {http://dx.doi.org/10.1038/s41436-018-0414-9},
  volume       = {21},
  year         = {2019},
}

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