July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Detection of clinically relevant genetic variants in nanophthalmos by whole genome sequencing
Author Affiliations & Notes
  • Zhigang Fan
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Congcong Guo
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Zhenni Zhao
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Denghui Chen
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Shuxiang He
    Guangzhou KingMed Diagnostics, China
  • Nannan Sun
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Zhongwen Li
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Jiafan Liu
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Dandan Zhang
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Jiamin Zhang
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Jianlong Li
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Miao Zhang
    ZHONGSHAN OPHTHALMIC CENTER, Guangzhan, China
  • Shihui Yu
    Guangzhou KingMed Diagnostics, China
  • Weiwei Zhao
    Guangzhou KingMed Diagnostics, China
  • Jingxing Liu
    Guangzhou KingMed Diagnostics, China
  • Xiaoling Zhang
    Section of Biomedical Genetics, Department of Medicine, Boston University School of Medicine, Massachusetts, United States
    Department of Biostatistics, Boston University School of Public Health, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Zhigang Fan, None; Congcong Guo, None; Zhenni Zhao, None; Denghui Chen, None; Shuxiang He, None; Nannan Sun, None; Zhongwen Li, None; Jiafan Liu, None; Dandan Zhang, None; Jiamin Zhang, None; Jianlong Li, None; Miao Zhang, None; Shihui Yu, None; Weiwei Zhao, None; Jingxing Liu, None; Xiaoling Zhang, None
  • Footnotes
    Support  Major Project of National Natural Science Foundation of China (NSFC)-Guangdong Province Joint Fund (Grant number: 3030902113080), Research Funds of the State Key Laboratory of Ophthalmology (Grant numbers: 30306020240020153, 30306020240020192, 3030902113058, 3030902113118), and Fundamental Research Funds of Sun Yat-sen University (Grant number: 16ykjc31)
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 403. doi:https://doi.org/
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    • Get Citation

      Zhigang Fan, Congcong Guo, Zhenni Zhao, Denghui Chen, Shuxiang He, Nannan Sun, Zhongwen Li, Jiafan Liu, Dandan Zhang, Jiamin Zhang, Jianlong Li, Miao Zhang, Shihui Yu, Weiwei Zhao, Jingxing Liu, Xiaoling Zhang; Detection of clinically relevant genetic variants in nanophthalmos by whole genome sequencing. Invest. Ophthalmol. Vis. Sci. 2019;60(9):403. doi: https://doi.org/.

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

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Abstract

Purpose : Nanophthalmos is a rare genetic disorder characterized commonly by short axial length (AL) and severe hyperopia. Mutations that have been identified through Mendelian genetic analysis can only explain a fraction of nanophthalmos cases. Here, we investigate the clinically relevant genetic variants in nanophthalmos by whole genome sequencing (WGS), including de novo mutations (DNMs) and inherited autosomal mutations.

Methods : The clinically relevant genetic variants of 11 trios (11 nanophthalmos probands and their unaffected parents) from Zhongshan Ophthalmic Center, China were analyzed through WGS.

Results : In 2 of 11 trios, without evidence of the presence of deleterious inherited autosomal variants, two DNMs of MYRF (c.789delC, p.S264fs and c.789dupC, p.S264fs) were identified in the probands, respectively, which were validated by Sanger sequencing (Fig.1). These loss-of-function DNMs were predicted to result in premature stop codons and protein structure damage in both probands. None of the DNMs were found in the following publicly population databases, including Genome Aggregation Database (gnomAD), Exome Sequencing Project 6500 (ESP6500siv2), and 1000 Genomes Project dataset (1000g). Furthermore, the gene co-expression and genetic interaction networks analyses demonstrated that MYRF had correlations with validated pathogenic genes of nanophthalmos (TMEM98), microphthalmia, anophthalmia and coloboma (PITX3 and BMP4), angle-closure glaucoma (GLIS3), and AL (RSPO1). In addition, deleterious inherited genetic variants in PRSS56 and MFRP were found in 8 probands of the other 9 trios (Fig.2). Among them, p.Gln356fs in PRSS56 and p.Asn167fs in MFRP have been reported in nanophthalmos cases.

Conclusions : This is the first trio-based WGS study for nanophthalmos, which reveals the potential role of DNMs and rare inherited genetic variants. In addition to inherited autosomal mutations in PRSS56 and MFRP, we report two novel frameshift DNMs in MYRF that suggest probably a mechanism, unknown so far, responsible for the development of nanophthalmos.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Fig.1 Two de novo mutations (DNMs) of MYRF were found. A. The DNM (MYRF: c.789delC, p.S264fs) in trio No.8. B. The DNM (MYRF: c.789dupC, p.S264fs) in trio No.10. Both of them were confirmed by Sanger sequencing.

Fig.1 Two de novo mutations (DNMs) of MYRF were found. A. The DNM (MYRF: c.789delC, p.S264fs) in trio No.8. B. The DNM (MYRF: c.789dupC, p.S264fs) in trio No.10. Both of them were confirmed by Sanger sequencing.

 

Fig.2 Pedigrees of families with nanophthalmos-relevant inherited autosomal variants.

Fig.2 Pedigrees of families with nanophthalmos-relevant inherited autosomal variants.

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