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.