De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases

Wei Li, Xiang Dong He, Zheng Tao Yang, Dong Ming Han, Yan Sun, Yan Xian Chen, Xiao Tong Han, Si Cheng Guo, Yu Ting Ma, Xin Jin, Huan Ming Yang, Ya Gao, Zhuo Shi Wang, Jian Kang Li, Wei He

Research output: Journal article publicationJournal articleAcademic researchpeer-review

3 Citations (Scopus)


PURPOSE. The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs). METHODS. To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing. RESULTS. All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia (n = 40%), Marfan syndrome/ectopia lentis (n = 38.78%), and retinoblastoma (n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal (P = 0.154) and maternal (P = 0.959) age at reproduction. CONCLUSIONS. Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.
Original languageEnglish
Article number5
Pages (from-to)1-10
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Issue number2
Publication statusPublished - 2 Feb 2023
Externally publishedYes


  • de novo mutation (DNM)
  • genetic landscape
  • inherited eye diseases (IED)
  • proband-parent trio
  • targeted exome sequencing

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience


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