Mutation Spectrum and De Novo Mutation Analysis in Stickler Syndrome Patients with High Myopia or Retinal Detachment

Huang, Li; Chen, Chonglin; Wang, Zhirong; Sun, Limei; Li, Songshan; Zhang, Ting; Luo, Xiaoling; Ding, Xiaoyan

doi:10.3390/genes11080882

Cited by 10 publications

(18 citation statements)

References 31 publications

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“…Exome libraries were enriched and sequenced on the Illumina HiSeq 2000 Genome Analyzer (Illumina, San Diego, CA, USA), using a HiSeq Sequencing Kit (Illumina) according to the manufacturer’s instructions. Bioinformatic analyses were made as described previously [ 34 , 35 , 36 , 37 ]. Based on the possible inheritance models of AF in the pedigree ( Figure 1 A), the variants that did not match any reasonable inheritance pattern of AF were filtered out.…”

Section: Methodsmentioning

confidence: 99%

KLF15 Loss-of-Function Mutation Underlying Atrial Fibrillation as well as Ventricular Arrhythmias and Cardiomyopathy

Shi

et al. 2021

Genes

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Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia and substantially increases the risks of cerebral stroke, heart failure and death. Accumulating evidence has convincingly demonstrated the strong genetic basis of AF, and an increasing number of pathogenic variations in over 50 genes have been causally linked to AF. Nevertheless, AF is of pronounced genetic heterogeneity, and the genetic determinants underpinning AF in most patients remain obscure. In the current investigation, a Chinese pedigree with AF as well as ventricular arrhythmias and hypertrophic cardiomyopathy was recruited. Whole exome sequencing and bioinformatic analysis of the available family members were conducted, and a novel heterozygous variation in the KLF15 gene (encoding Krüppel-like factor 15, a transcription factor critical for cardiac electrophysiology and structural remodeling), NM_014079.4: c.685A>T; p.(Lys229*), was identified. The variation was verified by Sanger sequencing and segregated with autosomal dominant AF in the family with complete penetrance. The variation was absent from 300 unrelated healthy subjects used as controls. In functional assays using a dual-luciferase assay system, mutant KLF15 showed neither transcriptional activation of the KChIP2 promoter nor transcriptional inhibition of the CTGF promoter, alone or in the presence of TGFB1, a key player in the pathogenesis of arrhythmias and cardiomyopathies. The findings indicate KLF15 as a new causative gene responsible for AF as well as ventricular arrhythmias and hypertrophic cardiomyopathy, and they provide novel insight into the molecular mechanisms underlying cardiac arrhythmias and hypertrophic cardiomyopathy.

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Section: Methodsmentioning

confidence: 99%

KLF15 Loss-of-Function Mutation Underlying Atrial Fibrillation as well as Ventricular Arrhythmias and Cardiomyopathy

Shi

et al. 2021

Genes

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“…It has an estimated prevalence of 1-3 in 10,000 [53]. This disorder can be caused by either AD inherited mutations of collagen type 2, collagen type 11, and lysyl oxidase or by AR inherited mutations in collagen type 9 and lysyl oxidase [13]. The most commonly seen mutations are in COL2A1 (STL type 1) and COL11A1 (STL type 2) [13].…”

Section: Stickler Syndromementioning

confidence: 99%

“…Ocular findings include myopia, cataracts, vitreous alterations, glaucoma, and retinal detachments (Table 3) [52,75]. Huang found that 76% had high myopia (>−6D), and 69% had retinal detachment, many of which had a COL2A1 mutation [13]. One study found in COL2A1 mutations that 89% had myopia, 42% had vitreous abnormalities, and 55% had at least one retinal detachment [52].…”

Section: Stickler Syndromementioning

confidence: 99%

“…However, the above risk factors may not be problematic for every person with an HDCT diagnosis. For example, reduced CCT is associated with specific gene sequence variants [3], and clinical presentation for each HDCT is variable and wide-ranging in symptom severity [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The exact rate of post-LASIK complications has been difficult to assess due to limited refractive surgery cases performed on those diagnosed with HDCTs.…”

Section: Introductionmentioning

confidence: 99%

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Controversy and Consideration of Refractive Surgery in Patients with Heritable Disorders of Connective Tissue

Moshirfar

Barke

Huynh

et al. 2021

JCM

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Heritable Disorders of Connective Tissue (HDCTs) are syndromes that disrupt connective tissue integrity. They include Osteogenesis Imperfecta (OI), Ehlers Danlos Syndrome (EDS), Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS), Epidermolysis Bullosa (EB), Stickler Syndrome (STL), Wagner Syndrome, and Pseudoxanthoma Elasticum (PXE). Because many patients with HDCTs have ocular symptoms, commonly myopia, they will often present to the clinic seeking refractive surgery. Currently, corrective measures are limited, as the FDA contraindicates laser-assisted in-situ keratomileusis (LASIK) in EDS and discourages the procedure in OI and MFS due to a theoretically increased risk of post-LASIK ectasia, poor wound healing, poor refractive predictability, underlying keratoconus, and globe rupture. While these disorders present with a wide range of ocular manifestations that are associated with an increased risk of post-LASIK complications (e.g., thinned corneas, ocular fragility, keratoconus, glaucoma, ectopia lentis, retinal detachment, angioid streaks, and ocular surface disease), their occurrence and severity are highly variable among patients. Therefore, an HDCT diagnosis should not warrant an immediate disqualification for refractive surgery. Patients with minimal ocular manifestations can consider LASIK. In contrast, those with preoperative signs of corneal thinning and ocular fragility may find the combination of collagen cross-linking (CXL) with either photorefractive keratotomy (PRK), small incision lenticule extraction (SMILE) or a phakic intraocular lens (pIOL) implant to be more suitable options. However, evidence of refractive surgery performed on patients with HDCTs is limited, and surgeons must fully inform patients of the unknown risks and complications before proceeding. This paper serves as a guideline for future studies to evaluate refractive surgery outcomes in patients with HDCTs.

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“…These variants cause a dominant-negative effect that dramatically impairs homotrimer assembly and stability, leading to growth bone alterations and severe phenotypes such as ACG2 and hypochondrogenesis. In contrast, nonsense mutations or out-of-frame deletions can cause a premature stop codon that leads to haploinsufficiency, resulting in a decrease in collagen synthesis, as well as diseases with milder phenotypes than that observed in ACG2 [7,11]. Splice site variants leading to an in-frame deletion of COL2A1 have already been described and are mainly associated with Kniest dysplasia [12,13].…”

Section: Introductionmentioning

confidence: 99%

A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions

Bruni

Spoleti

Barbera

et al. 2021

Genes

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Achondrogenesis type II (ACG2) is a lethal skeletal dysplasia caused by dominant pathogenic variants in COL2A1. Most of the variants found in patients with ACG2 affect the glycine residue included in the Gly-X-Y tripeptide repeat that characterizes the type II collagen helix. In this study, we reported a case of a novel splicing variant of COL2A1 in a fetus with ACG2. An NGS analysis of fetal DNA revealed a heterozygous variant c.1267-2_1269del located in intron 20/exon 21. The variant occurred de novo since it was not detected in DNA from the blood samples of parents. We generated an appropriate minigene construct to study the effect of the variant detected. The minigene expression resulted in the synthesis of a COL2A1 messenger RNA lacking exon 21, which generated a predicted in-frame deleted protein. Usually, in-frame deletion variants of COL2A1 cause a phenotype such as Kniest dysplasia, which is milder than ACG2. Therefore, we propose that the size and position of an in-frame deletion in COL2A1 may be relevant in determining the phenotype of skeletal dysplasia.

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Mutation Spectrum and De Novo Mutation Analysis in Stickler Syndrome Patients with High Myopia or Retinal Detachment

Cited by 10 publications

References 31 publications

KLF15 Loss-of-Function Mutation Underlying Atrial Fibrillation as well as Ventricular Arrhythmias and Cardiomyopathy

KLF15 Loss-of-Function Mutation Underlying Atrial Fibrillation as well as Ventricular Arrhythmias and Cardiomyopathy

Controversy and Consideration of Refractive Surgery in Patients with Heritable Disorders of Connective Tissue

A Novel Splicing Variant of COL2A1 in a Fetus with Achondrogenesis Type II: Interpretation of Pathogenicity of In-Frame Deletions

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