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. 2023 Feb 1;64(2):5.
doi: 10.1167/iovs.64.2.5.

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

Wei Li  1   2 , Xiang-Dong He  3 , Zheng-Tao Yang  1   2 , Dong-Ming Han  1   2 , Yan Sun  3 , Yan-Xian Chen  4 , Xiao-Tong Han  5 , Si-Cheng Guo  2   6 , Yu-Ting Ma  1   2 , Xin Jin  2 , Huan-Ming Yang  1   2 , Ya Gao  2 , Zhuo-Shi Wang  3 , Jian-Kang Li  2 , Wei He  3
Affiliations

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

Wei Li et al. Invest Ophthalmol Vis Sci. .

Abstract

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.

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Conflict of interest statement

Disclosure: W. Li, None; X.-D. He, None; Z.-T. Yang, None; D.-M. Han, None; Y. Sun, None; Y.-X. Chen, None; X.-T. Han, None; S.-C. Guo, None; Y.-T. Ma, None; X. Jin, None; H.-M. Yang, None; Y. Gao, None; Z.-S. Wang, None; J.-K. Li, None; W. He, None

Figures

Figure 1.
Figure 1.
Distribution and diagnostic yield of IED-causative genes. (A) A total of 107 IED-causative genes were identified, with the top 24 genes explained 67% of the 605 genetically solved trios. (B) Diagnosis yield and genes distribution in ASDs, PSDs, and other phenotypic categories. (C) Diagnosis yield and genes distribution in three categories of ASDs. (D) Diagnosis yield and genes distribution in six categories of PSDs. ASDs, anterior segment disorders; PSDs, posterior segment disorders; IRD, inherited retinal disease.
Figure 2.
Figure 2.
Number of trios and gene distribution of IED-causative DNMs in different subgroups.
Figure 3.
Figure 3.
(A) The distribution frequency of the genomewide high-confidence DNM per trio. (B) Enrichment of DNMs by variant class for all IEDs phenotypes, females and males probands. (C) Correlation between mother reproductive age and the incidence of DNM in offspring. (D) Correlation between father;s reproductive age and the incidence of DNM in offspring.
Figure 4.
Figure 4.
Statistics on the diagnostic yield of 22 IED subgroups. (A) Overall diagnostic yield solved by genetic testing in distinct subgroups. (B) Diagnostic yield solved by DNMs in distinct subgroups. (C) The proportion of DNM in overall diagnostic yield in distinct subgroups.
See this image and copyright information in PMC

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