PLoS ONE (Jan 2016)

De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa.

  • Samuel P Strom,
  • Michael J Clark,
  • Ariadna Martinez,
  • Sarah Garcia,
  • Amira A Abelazeem,
  • Anna Matynia,
  • Sachin Parikh,
  • Lori S Sullivan,
  • Sara J Bowne,
  • Stephen P Daiger,
  • Michael B Gorin

DOI
https://doi.org/10.1371/journal.pone.0150944
Journal volume & issue
Vol. 11, no. 3
p. e0150944

Abstract

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Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein-altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa.Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing.A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon.