Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant

Nathalie M Bax, Riccardo Sangermano, Susanne Roosing, Alberta A H J Thiadens, Lies H Hoefsloot, L Ingeborgh van den Born, Milan Phan, B Jeroen Klevering, Carla Westeneng-van Haaften, Terry A Braun, Marijke N Zonneveld-Vrieling, Ilse de Wijs, Merve Mutlu, Edwin M Stone, Anneke I den Hollander, Caroline C W Klaver, Carel B Hoyng, Frans P M Cremers

Research output: Contribution to journalArticleResearchpeer-review


Variants in ABCA4 are responsible for autosomal-recessive Stargardt disease and cone-rod dystrophy. Sequence analysis of ABCA4 exons previously revealed one causative variant in each of 45 probands. To identify the "missing" variants in these cases, we performed multiplex ligation-dependent probe amplification-based deletion scanning of ABCA4. In addition, we sequenced the promoter region, fragments containing five deep-intronic splice variants, and 15 deep-intronic regions containing weak splice sites. Heterozygous deletions spanning ABCA4 exon 5 or exons 20-22 were found in two probands, heterozygous deep-intronic variants were identified in six probands, and a deep-intronic variant was found together with an exon 20-22 deletion in one proband. Based on ophthalmologic findings and characteristics of the identified exonic variants present in trans, the deep-intronic variants V1 and V4 were predicted to be relatively mild and severe, respectively. These findings are important for proper genetic counseling and for the development of variant-specific therapies.

Original languageEnglish
Pages (from-to)43-7
Number of pages5
JournalHuman Mutation
Issue number1
Publication statusPublished - Jan 2015


  • ATP-Binding Cassette Transporters/genetics
  • Exons
  • Female
  • Genetic Association Studies/methods
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Introns
  • Macular Degeneration/congenital
  • Male
  • Pedigree
  • Retinitis Pigmentosa/genetics
  • Sequence Analysis, DNA
  • Sequence Deletion
  • Stargardt Disease


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