Mutation spectrum and genotype-phenotype correlations in Chinese congenital ectopia lentis patients

Guo, Dongwei; Jin, Guangming; Zhou, Yijing; Zhang, Xinyu; Cao, Qian; Lian, Zhangkai; Guo, Yinglu; Zheng, Danying

doi:10.1016/j.exer.2021.108570

Cited by 13 publications

(13 citation statements)

References 31 publications

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“…Three of these mutations (i.e., c.5065G>C (p.D1689H), c.1600T>A (p.534 S), and c.2210G>C (p.G737A)) were detected and correlated with EL for the first time and the remaining five (i.e., c.364C>T (p.R122C), c.1633C>T (p.R545C), and c.718C>T (p.R240C)) were previously reported. Our results are consistent with previous findings that congenital lens dislocations are most commonly caused by missense mutations in FBN1 (Guo et al, 2021). A previous study has shown that probands with missense mutations tend to exhibit high corneal astigmatism and severe lens dislocation, which is consistent with our current results (Guo et al, 2021).…”

Section: Discussionsupporting

confidence: 94%

Clinical and genetic findings in Chinese families with congenital ectopia lentis

Liu

Niu

Zhang

et al. 2023

Molec Gen & Gen Med

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Background: Congenital ectopia lentis (EL) refers to the congenital dysplasia or weakness of the lens suspensory ligament, resulting in an abnormal position of the crystalline lens, which can appear as isolated EL or as an ocular manifestation of a syndrome, such as the Marfan syndrome. The fibrillin-1 protein encoded by the FBN1 gene is an essential component of the lens zonules. Mutations in FBN1 are the leading causes of congenital EL and Marfan syndrome. Owing to the complexity and individual heterogeneity of FBN1 gene mutations, the correlation between FBN1 mutation characteristics and various clinical phenotypes remains unclear.Methods: This study describes the clinical characteristics and identifies possible causative genes in eight families with Marfan syndrome or isolated EL using Sanger and whole-exome sequencing.Results: Eight FBN1 mutations were identified in these families, of which three (c.5065G > C, c.1600 T > A, and c.2210G > C) are reported for the first time. Based on in silico analyses, we hypothesized that these mutations may be pathogenic by affecting the fibrillin-1 protein structure and function. Conclusion:These findings expand the number of known mutations involved in EL and provide a reference for the research on their genotype and phenotype associations.

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Section: Discussionsupporting

confidence: 94%

Clinical and genetic findings in Chinese families with congenital ectopia lentis

Liu

Niu

Zhang

et al. 2023

Molec Gen & Gen Med

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“…Early studies on genotype-phenotype correlation began with the susceptibility to EL and aortic dilatation ( Schrijver et al, 2002 ; Loeys et al, 2004 ). Later studies expanded the studied phenotypes to almost all aspects of the MFS manifestations, including the axial length of the eyeball ( Chen et al, 2021a ), astigmatism of the cornea ( Guo et al, 2021 ), severity of scoliosis ( Taniguchi et al, 2021 ), and incidence of ventricular tachycardia ( Aydin et al, 2013 ). Meanwhile, detailed parameters were applied instead of a broad description of aortic events, such as the aortic root diameters and the aortic stiffness ( Franken et al, 2017 ; Salvi et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…Contrary to aortic events, EL was more prevalent in patients harboring DN variants (Becerra-Muñoz et al, 2018;Li et al, 2019), especially the DN (-Cys) or DN (+Cys) ones (Faivre et al, 2007;Baudhuin et al, 2015;Meester et al, 2022). Chen et al and Guo et al further proved independently that DN variants were associated with a higher degree of EL compared to the HI ones in cohorts of congenital EL (Chen et al, 2021a;Guo et al, 2021). The variants associated with EL also cluster in the N-terminus of the FBN1 gene (Comeglio et al, 2007;Faivre et al, 2007;Baudhuin et al, 2015;Meester et al, 2022).…”

Section: Ocular Manifestationsmentioning

confidence: 99%

“…Posterior staphyloma and ciliary body cysts were more frequently observed in patients with variants in the C-terminus ( Chen et al, 2021a ). Patients with DN variants tend to show higher corneal astigmatism compared to HI variants ( Guo et al, 2021 ). The correlation between FBN1 variants and ocular features other than EL only received attention in a few studies, which demand further studies for verification.…”

Section: Genotype and Clinical Manifestationsmentioning

confidence: 99%

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Genotype-phenotype correlations of marfan syndrome and related fibrillinopathies: Phenomenon and molecular relevance

2022

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Marfan syndrome (MFS, OMIM: 154700) is a heritable multisystemic disease characterized by a wide range of clinical manifestations. The underlying molecular defect is caused by variants in the FBN1. Meanwhile, FBN1 variants are also detected in a spectrum of connective tissue disorders collectively termed as ‘type I fibrillinopathies’. A multitude of FBN1 variants is reported and most of them are unique in each pedigree. Although MFS is being considered a monogenic disorder, it is speculated that the allelic heterogeneity of FBN1 variants contributes to various manifestations, distinct prognoses, and differential responses to the therapies in affected patients. Significant progress in the genotype–phenotype correlations of MFS have emerged in the last 20 years, though, some of the associations were still in debate. This review aims to update the recent advances in the genotype-phenotype correlations of MFS and related fibrillinopathies. The molecular bases and pathological mechanisms are summarized for better support of the observed correlations. Other factors contributing to the phenotype heterogeneity and future research directions were also discussed. Dissecting the genotype-phenotype correlation of FBN1 variants and related disorders will provide valuable information in risk stratification, prognosis, and choice of therapy.

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“…The genetics of EL has become a fast‐growing research area. However, most studies have focused on the leading causal gene, FBN1 (MIM 134797), in Marfan syndrome (MIM 154700) and related fibrillinopathies (Guo et al, 2021; Zhou et al, 2021). Studies of non‐ FBN1 variants and their roles in congenital EL seem to be less prolific.…”

Section: Introductionmentioning

confidence: 99%

Biallelic ADAMTSL4 variants in a Chinese cohort of congenital ectopia lentis: Implications for genotype–phenotype relationships

et al. 2022

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ADAMTSL4 variants are one of the common causes of congenital ectopia lentis (EL), reported ocular comorbidities of which include iris anomalies, cataract, and glaucoma. However, a genotype-phenotype correlation has not been established.Potentially pathogenic ADAMTSL4 variants were screened from a Chinese cohort of congenital EL using panel-based next-generation sequencing followed by multiple bioinformatics analyses. The genotype-phenotype correlation was assessed via a systematic review of ADAMTSL4 variants within our data and those from the literature. A total of 12 variants of ADAMTSL4, including seven frameshift variants, one nonsense variant, two splicing variants, and two missense variants, were found in nine probands. Combing genetic and clinical information from 72 probands in the literature revealed 37 ADAMTSL4 variants known to cause EL, and the ethnic difference was prominent. The lens was inclined to dislocate inferior temporally (22, 27.16%), while the pupil was always located oppositely (9, 81.82%). Several anterior segments anomalies were identified, including ectopia pupillae (15, 18.52%), persistent pupillary membrane (9, 11.10%), poor pupil dilation (4, 30.8%), cataract (13, 24.10%), and glaucoma (8, 13.33%). Genotype-phenotype analysis revealed that truncation variants had higher risks of combined iris anomalies, including either ectopia pupillae or a persistent pupillary membrane (p = 0.007). The data from this study not only extend our knowledge of the ADAMTSL4 variant spectrum but also suggest that deleterious variants of ADAMTSL4 might be associated with severe ocular phenotypes.

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Mutation spectrum and genotype-phenotype correlations in Chinese congenital ectopia lentis patients

Cited by 13 publications

References 31 publications

Clinical and genetic findings in Chinese families with congenital ectopia lentis

Clinical and genetic findings in Chinese families with congenital ectopia lentis

Genotype-phenotype correlations of marfan syndrome and related fibrillinopathies: Phenomenon and molecular relevance

Biallelic ADAMTSL4 variants in a Chinese cohort of congenital ectopia lentis: Implications for genotype–phenotype relationships

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