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Mervyn George Thomas, Gail Maconachie, Rebecca McLean, Helen Kuht, Viral Sheth, Michael Hisaund, Swati Parida, Abdullah Aamir, Frank A Proudlock, Irene Gottlob; Whole Genome Sequencing in Infantile Nystagmus. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2350.
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© ARVO (1962-2015); The Authors (2016-present)
Infantile nystagmus is a genetically heterogenous disorder often arising from mutations of genes expressed within the developing neural retina and brain. Previously we have developed a nystagmus gene panel showing high levels of diagnostic accuracy and in some instances revising the clinical diagnosis.1 We successfully nominated to study infantile nystagmus as part of the 100,000 genomes project and currently spearhead the 100,000 genomes sub-project on the molecular genetics of infantile nystagmus. Therefore, in this study, we explore the value of whole genome sequencing together with our nystagmus gene panel. Specifically, we investigate the role of mutations of FRMD7 in the molecular pathogenesis of idiopathic infantile nystagmus (IIN) in a cohort of patients in UK and identify any mutation hotspots.
This prospective study looked at a population of infantile nystagmus presenting to University Hospitals of Leicester Trust, United Kingdom and other UK clinical centres participating in the 100,000 genomes study. Diagnosis of IIN was made based on normal ocular pigmentation and normal electrodiagnostic tests (visual evoked potentials and electroretinogram). DNA was extracted from saliva or blood samples. Sequencing was performed either using our nystagmus gene panel or whole genome sequencing (WGS) as part of the 100,000 genomes study. Pilot results from 120 patients are presented as part of this study.
62 FRMD7 mutations were identified in total. This included 39 novel mutations. Comparison with previous mutation data revealed 2 mutation hotspots. This included the recurring missense mutation c. 796G>C resulting in substitution alanine to proline at codon position 266, predicted to destabilise the FERM-C domain of the FRMD7 protein. Similarly, we identified a nonsense mutation hotspot c.1003C>T resulting in a premature stop codon at position 335, predicted to result in nonsense mediated decay. WGS revealed several novel deep intronic mutations predicted to alter splicing.
We expand on the mutation spectrum of FRMD7. This is the first study to report mutation hotspots in the FRMD7 gene and explore the utility of WGS in nystagmus. This has direct significance when devising a genetic testing strategy for IIN. However, a significant proportion of patients remain unsolved therefore further analysis of the WGS data will facilitate novel gene discovery.
This is a 2020 ARVO Annual Meeting abstract.
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