June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Long-read high-throughput sequencing uncovers rare structural variations in syndromic optic atrophy
Author Affiliations & Notes
  • Ren-Juan Shen
    Beijing Institute of Ophthalmology, Beijing, Beijing, China
    Beijing Tongren Hospital, Beijing, Beijing, China
  • Yang Li
    Beijing Institute of Ophthalmology, Beijing, Beijing, China
    Beijing Tongren Hospital, Beijing, Beijing, China
  • Zi-Bing Jin
    Beijing Institute of Ophthalmology, Beijing, Beijing, China
    Beijing Tongren Hospital, Beijing, Beijing, China
  • Footnotes
    Commercial Relationships   Ren-Juan Shen None; Yang Li None; Zi-Bing Jin None
  • Footnotes
    Support  Beijing Natural Science Foundation (Z200014) , National Natural Science Foundation of China (82125007)
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 502 – A0079. doi:
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    • Get Citation

      Ren-Juan Shen, Yang Li, Zi-Bing Jin; Long-read high-throughput sequencing uncovers rare structural variations in syndromic optic atrophy. Invest. Ophthalmol. Vis. Sci. 2022;63(7):502 – A0079.

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

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Abstract

Purpose : Next generation sequencing (NGS), that is, short-read sequencing (SRS), has been widely used in identifying pathogenic mutations in inherited eye diseases (IEDs). However, the approximate diagnosis rate using SRS is around 52%, which is probably due to novel genes, or variants that may be missed by SRS approaches, such as structural variants (SVs) and variants in introns or regulatory regions. In this study, we performed long-read sequencing (LRS) to re-evaluate the disease-causing mutations of IED patient whose genetic etiology remained unclear after SRS.

Methods : Long read sequencing around 30X genome coverage using the PacBio Sequel II system was performed on a Chinese family with a proband diagnosed with syndromic optic atrophy. Comprehensive bioinformatic analysis was then conducted, followed by trio-based segregation analysis and pathogenicity analysis.

Results : Genome-wide SV calling yielded a total of 130520 SVs, with de novo SVs of 12188. Among them, we determined a novel 1447-bp de novo heterozygous deletion located in the NR2F1 gene which was segregated with the phenotype of optic atrophy and epilepsy. The de novo deletion spans the 5’ UTR and the first exon along with partial intron 1, resulting in haploinsufficiency of NR2F1,which has been reported to be the etiology of autosomal dominant Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS).

Conclusions : The genetic etiology of the family with syndromic optic atrophy was successfully identified using LRS and we reported a novel SV associated with BBSOAS. Overall, this study has shown that SVs may contribute to the genetic etiology of syndromic optic atrophy, and that SV analyses should be included in the genetic workflow of IED. It also demonstrates the potential value of long-read sequencing in identifying SVs in patients with IEDs.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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