Next‐generation sequencing targeted disease panel in rod‐cone retinal dystrophies in Māori and Polynesian reveals novel changes and a common founder mutation

Importance This study identifies unique genetic variation observed in a cohort of Māori and Polynesian patients with rod‐cone retinal dystrophies using a targeted next‐generation sequencing retinal disease gene panel. Background With over 250 retinal disease genes identified, genetic diagnosis is still only possible in 60–70% of individuals and even less within unique ethnic groups. Design Prospective genetic testing in patients with rod‐cone retinal dystrophies identified from the New Zealand Inherited Retinal Disease Database, Participants Sixteen patients of Māori and Polynesian ancestry. Methods Next‐generation sequencing of a targeted retinal gene panel. Sanger sequencing for a novel PDE6B mutation in subsequent Māori patients. Main Outcome Measures Genetic diagnosis, genotype–phenotype correlation. Results Thirteen unique pathogenic variants were identified in 9 of 16 (56.25%) patients in 10 different genes. A definitive genetic diagnosis was made in 7/16 patients (43.7%). Six changes were novel and not in public databases of human variation. In four patients, a homozygous, novel pathogenic variant (c.2197G > C, p.(Ala 733Pro)) in PDE6B was identified and also present in a further five similarly affected Māori patients. Conclusions and Relevance Over half of the Māori and Polynesian patients with inherited rod‐cone diseases have no pathogenic variant(s) detected with a targeted retinal next‐generation sequencing strategy, which is supportive of novel genetic mechanisms in this population. A novel PDE6B founder variant is likely to account for 16% of recessive inherited retinal dystrophy in Māori. Careful characterization of the clinical presentation permits identification of further Māori patients with a similar phenotype and simplifies the diagnostic algorithm.