Fibrillin-1 gene mutations in a Chinese cohort with congenital ectopia lentis: spectrum and genotype-phenotype analysis

Abstract

Aims: To identify the mutation spectrum and genotype-phenotype correlations of fibrillin-1 (FBN1) mutations in a Chinese cohort with congenital ectopia lentis (EL).

Methods: Patients clinically suspected of congenital zonulopathy were screened using panel-based next-generation sequencing followed by multiplex ligation-dependent probe amplification. All the probands were subjected to thorough ocular examinations. Molecular and clinical data were integrated in pursuit of genotype-phenotype correlation.

Results: A total of 131 probands of FBN1 mutations from unrelated families were recruited. Around 65% of the probands were children younger than 9 years old. Overall, 110 distinct FBN1 mutations were identified, including 39 novel ones. The most at-risk regions were exons 13, 2, 6, 15, 24 and 33 in descending order of mutation frequency. The most prevalent mutation was c.184C>T (seven, 5.34%) in the coding sequence and c.5788+5G>A (three, 2.29%) in introns. Missense mutations were the most frequent type (103, 78.63%); half of which were distributed in the N-terminal regions (53, 51.46%). The majority of missense mutations were detected in one of the calcium-binding epidermal growth factor-like domains (62, 60.19%), and 39 (62.90%) of them were substitutions of conserved cysteine residues. Microspherophakia (MSP) was found in 15 patients (11.45%). Mutations in the middle region (exons 22-42), especially exon 26, had higher risks of combined MSP (OR, 5.51 (95% CI 1.364 to 22.274), p=0.017).

Conclusions: This study extended the knowledge of the FBN1 mutation spectrum and provided novel insights into its clinical correlation regarding EL and MSP in the Chinese population.

Keywords: genetics; lens and zonules.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Photos of congenital zonulopathy caused by fibrillin-1 mutations. (A) One eye of a patient (c.1709G>C) with EL and smooth lens edge. The lens was dislocated superior nasally. (B) One eye of a patient (c.3476G>T) with EL and MSP. The lens was thicker, and the entire equator was visible when the pupil was fully dilated. The superior equator is hidden because of combined EL. (C) One eye of a patient (c.290C>G) with coloboma lentis. A notch in the lens tissue at the equator was observed inferior temporally. (D) One eye of a patient (c.5885_5895del) with EL and an irregular lens edge at the temporal side. EL, ectopia lentis; MSP, microspherophakia.

Figure 2

Structural distribution of fibrillin-1 (FBN1) mutations (including recurrent mutations). (A) Frequency of FBN1 mutations per exon and the corresponding N-terminal (exons 1–21), middle (exons 22–42) and C-terminal (exons 43–65) regions. (B) Frequency of FBN1 mutations per intron. (C) Frequency of FBN1 mutations per amino acid and the corresponding protein domains. Hotspots are noted.cb, calcium binding; COOH; carboxyl; EGF, epidermal growth factor; LTBP, latent transforming growth factor β binding protein; NH2, amino; TGFBP, transforming growth factor β binding protein.

Figure 3

Genetic analyses of the fibrillin-1 (FBN1) mutations identified in 131 probands with zonulopathy. (A) Proportions of FBN1 mutations of all probands classified as missense mutations, frameshift mutations, nonsense mutations, splicing mutations, in-frame deletions or insertions, complex mutations and intragenic deletion/duplication. (B) Proportions of FBN1 missense mutation amino acid changes classified as cysteine (Cys)-creating, Cys-eliminating and changes involving other amino acids. (C) Proportions of FBN1 missense mutations mapped to coding sequences in the N-terminal (exons 1–21), middle (exons 22–42) and C-terminal (exons 43–65) regions. (D) Proportions of FBN1 missense mutations mapped to EGF-like domain, cb-EGF-like domain, TGFBP domain, 4-Cys motif LTBP-like domain, hybrid module and other protein domains. (E) Heatmap showing the frequency of Cys-creating, Cys-eliminating and other types of amino acid changes in different protein domains. cb, calcium binding; EGF, epidermal growth factor; LTBP, latent transforming growth factor β binding protein; TGFBP, transforming growth factor β binding protein.

Figure 4

Genotype–phenotype analysis of patients with and without MSP. (A) Comparison of type of mutation, amino acid change, protein domain and mutation sites in patients with EL alone or EL complicated by MSP. (B) Comparison of mutation spectrum by cluster analysis in patients with EL alone or EL complicated by MSP. Heatmap of fibrillin-1 mutations shows the number of missense mutations per exons and splicing mutations per introns. Exon 26 is marked by a red asterisk. Cys, cysteine; EL, ectopia lentis; EL − MSP, patients with EL but not MSP; EL+ MSP, patients with EL and MSP; EX, exon; Cys, MSP, microspherophakia. cb, calcium binding; EGF, epidermal growth factor; LTBP, latent transforming growth factor β binding protein; TGFBP, transforming growth factor β binding protein.