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. 2025 Apr 9;19(1):38.
doi: 10.1186/s40246-025-00749-2.

Reliability of clinical impressions and optimal genetic diagnostic strategies of heritable connective tissue disorders with ocular involvement in a large Chinese cohort

Qin-Meng Shu #  1   2   3 , Yu-Qiao Ju #  1   2   3 , Yuan Zong  1   2   3 , Ting Zhang  1   2   3 , Xin Huang  4   5   6 , Feng-Juan Gao  7   8   9 , Qing Chang  10   11   12
Affiliations

Reliability of clinical impressions and optimal genetic diagnostic strategies of heritable connective tissue disorders with ocular involvement in a large Chinese cohort

Qin-Meng Shu et al. Hum Genomics. .

Abstract

Purpose: This study aimed to elucidate the reliability of clinical impressions based on ocular manifestations in patients suspected of heritable connective tissue disorders (HCTDs) compared to the final genetic diagnosis. Furthermore, it sought to determine the optimal diagnostic strategy for patients with HCTDs through pathogenicity analysis.

Methods: Clinical characteristics of 58 patients suspected of HCTDs were analyzed to establish provisional clinical diagnoses. Subsequently, next-generation sequence and Sanger sequence was performed to obtain genetic diagnoses. Pathogenicity of identified variants was assessed through conservation analysis and the functional impact, which was predicted using three-dimensional protein structure modeling.

Results: The provisional clinical diagnosis was concordant with the molecular diagnostic result in only 21 patients. Independent of the initial clinical impression, a probable genetic diagnosis was achieved for all 58 patients following comprehensive re-analysis of next-generation sequence data, combined with pathogenicity assessment using three-dimensional protein structure and conservation analysis of suspicious positive variants.

Conclusion: This study broadens the mutational spectrum of HCTDs with 31 novel variants. By employing innovative methodologies to delineate phenotype-genotype relationships, including the detection of potentially pathogenic variants, this work may inform future diagnostic strategies and guide comprehensive disease and organ system monitoring. Ongoing refinement and vigilant clinical oversight remain essential for patients and their families.

Keywords: Genetic diagnosis; Heritable connective tissue disorders; Knobloch syndrome; Severe myopia; Stickler syndrome; Wagner syndrome.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Approval for data collection and analysis was granted by the Institutional Review Board of the Eye and ENT Hospital of Fudan University, Shanghai, China on November 26, 2020. The ethical approval number was [2020]2020119. Informed consent was obtained from all individual participants or their parents or legal guardian in the case of children under 16 included in the study. Consent for publication: All authors read and approved the final manuscript. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The predicted effect of variants rated as VUS in 3D protein structures. A and B present the 3D structures of six wild-type proteins: COL2A1, COL11A1, COL18A1, VCAN, FBN1 and P3H2. From C to H, “Merge” represents the superposition before and after mutation, with green representing the wild type and blue representing the mutant type
Fig. 2
Fig. 2
Multiple sequence alignment of the 15 missense variants rated as VUS from different species. Species name cross-reference: Homo sapiens, human; Mus musculus, house mouse; Rattus norvegicus, Norway rat; Bos taurus, domestic cattle; Pan troglodytes, chimpanzee; Canis lupus familiaris, dog; Macaca mulatta, Rhesus monkey; Macaca nemestrina, pig-tailed macaque; Mandrillus leucophaeus, drill; Cercocebus atys, sooty mangabey; Theropithecus gelada, gelada. “*” indicates high conservatism in the species
Fig. 3
Fig. 3
Clinical manifestations in heritable connective tissue diseases.
See this image and copyright information in PMC

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Supplementary concepts