Trio-based exome sequencing broaden the genetic spectrum in keratoconus

Xu, Liyan; Yang, Kaili; Zhu, Meng; Yin, Shanshan; Gu, Yuwei; Fan, Qi; Wang, Yawen; Pang, Chenjiu; Ren, Shuxin

doi:10.1016/j.exer.2022.109342

Cited by 8 publications

(10 citation statements)

References 46 publications

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“…Furthermore, we summarized the BCORL1 variants that are associated with human diseases retrieved from pubmed (https://pubmed.ncbi.nlm.nih.gov/) (Figure S2, Table S1). We noticed that a BCORL1 variant (c.G2669A:p.R890Q) was identified in two unrelated male patients with different phenotypes, one with biliary atresia 26 and the other with conotruncus 27 . Interestingly, in our study, the same variant M3 (c.2669G > A:p.R890Q) was identified in one subject with OAT and in another subject with NOA.…”

Section: Discussionsupporting

confidence: 58%

“…We noticed that a BCORL1 variant (c.G2669A:p.R890Q) was identified in two unrelated male patients with different phenotypes, one with biliary atresia 26 and the other with conotruncus. 27 Interestingly, in our study, the same variant M3 (c.2669G > A:p.R890Q) was identified in one subject with OAT and in another subject with NOA. These findings suggested that the same variant in BCORL1 can be associated with multiple phenotypes.…”

Section: Discussionsupporting

confidence: 50%

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A hemizygous loss‐of‐function variant in BCORL1 is associated with male infertility and oligoasthenoteratozoospermia

Luo,

Chen,

Meng

et al. 2024

Clinical Genetics

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Oligoasthenoteratozoospermia (OAT) is a common type of male infertility; however, its genetic causes remain largely unknown. Some of the genetic determinants of OAT are gene defects affecting spermatogenesis. BCORL1 (BCL6 corepressor like 1) is a transcriptional corepressor that exhibits the OAT phenotype in a knockout mouse model. A hemizygous missense variant of BCORL1 (c.2615T > G:p.Val872Gly) was reported in an infertile male patient with non‐obstructive azoospermia (NOA). Nevertheless, the correlation between BCORL1 variants and OAT in humans remains unknown. In this study, we used whole‐exome sequencing to identify a novel hemizygous nonsense variant of BCORL1 (c.1564G > T:p.Glu522*) in a male patient with OAT from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S‐phase kinase‐associated protein 1). Further population screening identified four BCORL1 missense variants in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%), but no pathogenic BCORL1 variants among 362 fertile subjects. In conclusion, our findings indicate that BCORL1 is a potential candidate gene in the pathogenesis of OAT and NOA, expanded its disease spectrum and suggested that BCORL1 may play a role in spermatogenesis by interacting with SKP1.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionsupporting

confidence: 50%

A hemizygous loss‐of‐function variant in BCORL1 is associated with male infertility and oligoasthenoteratozoospermia

Luo,

Chen,

Meng

et al. 2024

Clinical Genetics

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“…In addition, exome sequencing identified SLC35E2B variants in Central European families with high myopia ( Swierkowska et al, 2021 ). Trio-based exome sequencing identified TNRC6A variants in keratoconus, a genetic disease causing myopia and astigmatism ( Xu et al, 2023 ). In addition, PROM1 mutations were reported to cause cone-rod dystrophy with high myopia and nystagmus ( Khan and Bolz, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Epitranscriptomic investigation of myopia-associated RNA editing in the retina

Pan

et al. 2023

Front. Neurosci.

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Myopia is one of the most common causes of vision loss globally and is significantly affected by epigenetics. Adenosine-to-inosine (A-to-I RNA) editing is an epigenetic process involved in neurological disorders, yet its role in myopia remains undetermined. We performed a transcriptome-wide analysis of A-to-I RNA editing in the retina of form-deprivation myopia mice. Our study identified 91 A-to-I RNA editing sites in 84 genes associated with myopia. Notably, at least 27 (32.1%) of these genes with myopia-associated RNA editing showed existing evidence to be associated with myopia or related ocular phenotypes in humans or animal models, such as very low-density lipoprotein receptor (Vldlr) in retinal neovascularization and hypoxia-induced factor 1 alpha (Hif1a). Moreover, functional enrichment showed that RNA editing enriched in FDM was primarily involved in response to fungicides, a potentially druggable process for myopia prevention, and epigenetic regulation. In contrast, RNA editing enriched in controls was mostly involved in post-embryonic eye morphogenesis. Our results demonstrate altered A-to-I RNA editing associated with myopia in an experimental mouse model and warrant further study on its role in myopia development.

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“…Using Alamut, it was found that the variant affects the canonical splicing site and generates a new donor site that could compromise the structure and function of the protein. NDRG1 (OMIM: #605262) is also an important regulator of the VEFG factor that is essential for the maintenance of the balance between anti-angiogenic and angiogenic factors to maintain corneal avascularity and transparency, relevant in the development of keratoconus [40].…”

mentioning

confidence: 99%

“…Recently, the literature has raised the possibility of a link between TTN and the etiology of keratoconus by inducing corneal thinning. In studies performed using trio-exome NGS, variants in this gene appeared in approximately 25% of those affected, thus suggesting that mutated TTN is a risk factor in the disease [40]. The TTN gene codes for the largest protein in the human body, titin, which is involved in regulating the organization of the cytoskeleton in cardiomyocytes.…”

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confidence: 99%

Whole-Exome Sequencing of 24 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Keratoconus

González-Atienza,

Sánchez-Cazorla,

Villoldo-Fernández

et al. 2023

Genes

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Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients. The presentation of this disease in pediatric age is associated with rapid progression, a worse prognosis and, in 15–20% of cases, the need for corneal transplantation. It is a multifactorial disease with genetic variability, which makes its genetic study difficult. Discovering new therapeutic targets is necessary to improve the quality of life of patients. In this manuscript, we present the results of whole-exome sequencing (WES) of 24 pediatric families diagnosed at the University Hospital La Paz (HULP) in Madrid. The results show an oligogenic inheritance of the disease. Genes involved in the structure, function, cell adhesion, development and repair pathways of the cornea are proposed as candidate genes for the disease. Further studies are needed to confirm the involvement of the candidate genes described in this article in the development of pediatric keratoconus.

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Trio-based exome sequencing broaden the genetic spectrum in keratoconus

Cited by 8 publications

References 46 publications

A hemizygous loss‐of‐function variant in BCORL1 is associated with male infertility and oligoasthenoteratozoospermia

A hemizygous loss‐of‐function variant in BCORL1 is associated with male infertility and oligoasthenoteratozoospermia

Epitranscriptomic investigation of myopia-associated RNA editing in the retina

Whole-Exome Sequencing of 24 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Keratoconus

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