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Andrea L Vincent, Nandoun Abeysekera, Katherine van Bysterveldt, Verity Frances Oliver, Graeme C.M. Black; Novel Genotype-Phenotype correlations in a Māori and Polynesian Population with Autosomal Recessive Inherited Retinal Disease, using a Next Generation Targeted Retinal Panel.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2899.
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© ARVO (1962-2015); The Authors (2016-present)
To phenotypically characterize presumed autosomal recessive rod-cone retinal dystrophies (ARRP) in Māori and Polynesian patients with no previous identified gene mutation; to elucidate the gene mutations which are associated with retinal dystrophies in this population, and to establish phenotype-genotype correlations.
Thirty-six patients of Māori and Polynesian ancestry with no causative mutation detected on disease microarrays (Asper, Estonia), were identified from the Inherited Retinal and Optic Nerve Disorders Database. Clinical history and examination, pedigrees, OCT, fundal photography, fundus autofluorescence, and electrophysiology were obtained and reviewed for each patient. DNA of 15 of these patients with presumed ARRP underwent Next Generation Sequencing of a targeted retinal disease gene panel (NGS-TRDGP). An ethnically matched control population was screened for identified changes. Subsequent patients seen with a similar phenotype were tested for the novel change.
Of the Māori and Polynesian patients studied, probable disease-causing mutations were detected in 40% using NGS-TRDGP: this included a hemizygous RPGR mutation (n=1), heterozygous CRX (n=1), and a novel homozygous PDE6B mutation, predicted to be deleterious (n=4, all New Zealand Māori). The phenotype in these patients is consistent with previously described PDE6B -associated disease. This change was present in 1/124 an ethnically matched alleles. Identification of 3 subsequent Māori patients with a similar phenotype to that observed with PDE6B, has confirmed the same homozygous PDE6B variant.
NGS is a superior technique to other commercially available techniques for causative gene mutations in ARRP. The majority of Māori and Polynesian patients tested have no disease causing pathogenic variant(s) detected, which is strongly supportive of novel genetic mechanisms causative of disease in this population. The novel PDE6B mutation, is not in high frequency in a Māori control population, and predicted to be deleterious. The phenotype-genotype correlation allows identification of the likely causative gene, resulting in targeted and cost effective gene screening. Within the Māori and Polynesian population there are still unknown genetic mechanisms accounting for the majority of disease.
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