June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Next-generation sequencing of the complete mitochondrial genome in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA mutations
Author Affiliations & Notes
  • Srilekha Sundaramurthy
    SNONGC Genetics & Molecular Biology, Vision Research Foundation, Chennai, Tamil Nadu, India
  • Ambika Selvakumar
    Department of Neuro-Ophthalmology, Medical Research Foundation, India
  • Vidhya Dharani
    Department of Neuro-Ophthalmology, Medical Research Foundation, India
  • Mathavan Sinnakaruppan
    SNONGC Genetics & Molecular Biology, Vision Research Foundation, Chennai, Tamil Nadu, India
  • Sripriya Sarangapani
    SNONGC Genetics & Molecular Biology, Vision Research Foundation, Chennai, Tamil Nadu, India
  • Patrick Yu-Wai-Man
    Cambridge University Hospitals, Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge, United Kingdom
    Department of Clinical Neurosciences, University of Cambridge, John Van Geest Centre for Brain Repair, Cambridge, United Kingdom
  • Footnotes
    Commercial Relationships   Srilekha Sundaramurthy, None; Ambika Selvakumar, None; Vidhya Dharani, None; Mathavan Sinnakaruppan, None; Sripriya Sarangapani, None; Patrick Yu-Wai-Man, None
  • Footnotes
    Support  NONE
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 5183. doi:
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      Srilekha Sundaramurthy, Ambika Selvakumar, Vidhya Dharani, Mathavan Sinnakaruppan, Sripriya Sarangapani, Patrick Yu-Wai-Man; Next-generation sequencing of the complete mitochondrial genome in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA mutations. Invest. Ophthalmol. Vis. Sci. 2020;61(7):5183.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Reports from populations of different geographic backgrounds show that about 90% percent of individuals with Leber hereditary optic neuropathy (LHON) harbour one of the three (primary) mitochondrial DNA (mtDNA) point mutations: m.3460G>A (MT-ND1), m.11778G>A (MT-ND4) or m.14484T>C (MT-ND6). The purpose of this study was to screen the whole mitochondrial genome of LHON patients negative for these three common mtDNA mutations to investigate the role of other mtDNA variants in the pathogenesis of this blinding optic neuropathy.

Methods : Twenty-four individuals who were clinically suspected to have LHON were recruited from the Neuro-Ophthalmology Clinic (Medical Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India). A comprehensive neuro-ophthalmic examination, including slit lamp examination, indirect ophthalmoscopy and visual field perimetry was performed. Targeted re-sequencing using next-generation sequencing (NGS) on the HiSeq X Ten platform (Illumina, San Diego, California) using a 2×150bp paired-end setting. The variants were filtered using VARIMAT tool (v.2.3.9) and the haplogroup analysis was performed using haplogrep 2 tool (v2.0).

Results : Whole mitochondrial genome sequencing of 24 clinically suspected cases of LHON revealed a total of 860 variants of which 440 variants were present in the coding region and 292 were synonymous mutations. We have identified secondary mtDNA variants in eight individuals (8/24, 33.3%) with variants in MTND1 being the most common (5/24, 20.0%). The m.4216T>C variant in MTND1 was found in three unrelated cases, but its pathological significance needs to be validated by screening a control group in our ethnic population (currently ongoing).The majority of individuals belonged to haplogroup M (n= 13), followed by haplogroup R (n=6) and haplogroup U (n=5). Additional cases of LHON are being recruited for whole mitochondrial genome sequencing in order to further explore whether there are different set of mtDNA variants causing LHON in the Indian population.

Conclusions : This study on a well-characterised Indian LHON cohort negative for the three primary mtDNA mutations has revealed secondary mtDNA variants which should be considered during the evaluation of optic atrophy cases. The MTND1 subunit gene could be a mutational hotspot for LHON in the Indian population.

This is a 2020 ARVO Annual Meeting abstract.

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