<i>De Novo</i> Occurrence of a Variant in <i>ARL3</i> and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa

<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results and Conclusions</p><p>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 <i>ARL3</i>. Follow-up testing established that this variant occurred <i>de novo</i> in the index case. No additional putative causal variants in <i>ARL3</i> were identified in the follow-up cohort, suggesting that if <i>ARL3</i> variants can cause adRP it is an extremely rare phenomenon.</p>