Key Takeaways & Executive Findings
- •• Identified four novel PITX2 variants in Chinese ARS families, including two frameshift, one nonsense, and one splice-site mutation. • All variants co-segregated with the disease phenotype in an autosomal dominant pattern, with two occurring de novo. • The variants are absent from population databases, confirming their rarity and likely pathogenicity. • This study expands the mutational spectrum of PITX2 and provides a basis for genetic counseling and functional studies.
Abstract
Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder characterized by anterior segment dysgenesis and systemic features. PITX2 variants are a major cause. In this study, we recruited four unrelated Chinese families with ARS and performed Sanger sequencing of PITX2. We identified four heterozygous variants: c.118delA (p.Arg40Glyfs*115), c.211G>T (p.Glu71X), c.253-1G>T, and c.663_670dupGACTCCTC (p.Pro224Argfs*18). These variants co-segregated with the phenotype in an autosomal dominant pattern, with two arising de novo. All variants were absent from ExAC and gnomAD, indicating rarity. Our findings expand the mutation spectrum of PITX2 and provide insights into the molecular mechanisms of ARS.
1. Introduction
Axenfeld-Rieger syndrome (ARS), initially characterized by Theodor Axenfeld and Herwigh Rieger in the early 20th century [1], is a rare genetic disorder with an estimated prevalence of 1:200,000 in live births [2]. This condition is characterized by distinctive anterior segment dysgenesis, including iris stromal hypoplasia, corectopia, and posterior embryotoxon. It is also accompanied by characteristic systemic features such as craniofacial dysmorphism, dental anomalies, cardiovascular malformations, and periumbilical skin redundancy [3,4].
Genetically, ARS is highly heterogeneous, with pathogenic variants identified in several genes. Among these, PITX2 on chromosome 4q25 [5] and FOXC1 on chromosome 6p25 [6] are the most frequently implicated. In particular, PITX2 is a transcription factor harboring a highly conserved homeobox domain, which regulates the transcription of downstream targets essential for ocular, dental, cardiac, and umbilical development [7,8]. Variants in PITX2 may alter protein localization or impair its transcriptional activity, thereby disrupting normal developmental processes and leading to the characteristic phenotypes of ARS [9,10].
Despite its clinical and genetic significance, ARS is thought to be underdiagnosed, and most studies on PITX2-related ARSs remain limited to individual case reports. In the present study, we aimed to delineate the genetic spectrum of ARS in Chinese patients and to elucidate the molecular mechanisms underlying the pathogenesis associated with PITX2 variants.
Loading authentic research manuscript (Pages 1–5)...
Junqin Xu, Xinyao Wang, Zilin Zhong, Jianjun Chen, Peng Yang (2026). Genetic characterization and functional analysis of novel PITX2 variants identified in Chinese families with Axenfeld-Rieger syndrome. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025167
Research & Educational Purpose Only:The translations, structured abstracts, analytical annotations, and data reports provided by SinoBioData are intended exclusively for academic research, internal corporate R&D, and educational benchmarking. They do not constitute formal engineering, chemical safety, legal, or professional advice.
Copyright & Intellectual Property Notice: Original copyright of the underlying source articles and experimental data remains with the respective authors, institutions, and original publishing journals. SinoBioData claims intellectual property only over its proprietary translations, analytical syntheses, and AEO structured enhancements in accordance with international fair use and academic citation principles.
Frequently Asked Questions
What is Axenfeld-Rieger syndrome?
Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder characterized by anterior segment dysgenesis of the eye, along with systemic features such as craniofacial, dental, cardiac, and umbilical anomalies. It is caused by mutations in genes like PITX2 and FOXC1.
What novel PITX2 variants were identified in this study?
The study identified four novel PITX2 variants in Chinese ARS families: c.118delA (p.Arg40Glyfs*115), c.211G>T (p.Glu71X), c.253-1G>T, and c.663_670dupGACTCCTC (p.Pro224Argfs*18). These include frameshift, nonsense, and splice-site mutations.
How were the PITX2 variants identified?
Genomic DNA was extracted from blood samples of probands and family members. Specific primers for PITX2 were designed, and PCR products were analyzed by Sanger sequencing to detect variants.
What is the inheritance pattern of the identified variants?
The variants co-segregated with the disease phenotype in an autosomal dominant pattern, affecting both males and females. Two of the variants arose de novo, indicating sporadic cases.
Why are these findings significant?
These findings expand the mutation spectrum of PITX2 in ARS, provide insights into the molecular mechanisms, and have implications for genetic counseling and diagnosis of ARS in Chinese populations.
Related Technical Papers & Translations
Adverse Events Reporting System for Vaccine Safety Surveillance: A Comprehensive Analysis
Background: Adverse events following immunization (AEFI) are critical to monitor for vaccine safety. This study evaluates the performance of an adverse events reporting system (AERS) integrated with a vaccine adverse event reporting system (VAERS) to enhance surveillance. Methods: We analyzed data from multiple sources including the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) network. A novel framework was developed to integrate these systems, incorporating natural language processing for signal detection. Results: The integrated system improved detection of rare adverse events by 25% compared to traditional methods. The system identified new safety signals for influenza and COVID-19 vaccines. Conclusions: The proposed AERS framework enhances vaccine safety surveillance, enabling timely identification of potential risks. Integration of diverse data sources and advanced analytics is essential for robust pharmacovigilance.
Efficacy and Safety of Ferric Carboxymaltose in Treating Iron Deficiency Anemia: A Meta-Analysis of Randomized Controlled Trials
Background: Iron deficiency anemia (IDA) is a global health concern, and intravenous ferric carboxymaltose (FCM) has emerged as a promising treatment. This meta-analysis aimed to evaluate the efficacy and safety of FCM compared to other iron therapies or placebo in adults with IDA. Methods: We systematically searched PubMed, Embase, and Cochrane Library up to December 2024. Randomized controlled trials (RCTs) comparing FCM with active comparators or placebo in adults with IDA were included. The primary outcomes were change in hemoglobin (Hb) from baseline, and safety outcomes included adverse events (AEs) and serious adverse events (SAEs). Pooled estimates were calculated using random-effects models. Results: A total of 15 RCTs involving 4,856 patients were included. FCM significantly increased Hb levels compared to placebo (mean difference [MD] 1.2 g/dL, 95% CI 0.9-1.5) and was non-inferior to other intravenous iron preparations. The risk of AEs was similar between FCM and comparators (risk ratio [RR] 1.05, 95% CI 0.95-1.16), but FCM was associated with a lower risk of gastrointestinal AEs compared to oral iron. Serious adverse events were rare and comparable across groups. Conclusion: Ferric carboxymaltose is effective and safe for treating IDA, offering a convenient single-dose option with a favorable safety profile. These findings support its use in clinical practice.
Adverse Drug Reactions Associated with COVID-19 Vaccination: A Systematic Review and Meta-Analysis
Background: The rapid development and deployment of COVID-19 vaccines have been crucial in controlling the pandemic. However, adverse drug reactions (ADRs) associated with these vaccines have raised concerns. This systematic review and meta-analysis aimed to comprehensively evaluate the incidence and types of ADRs following COVID-19 vaccination. Methods: We systematically searched PubMed, Embase, and Cochrane Library from inception to December 2024. Randomized controlled trials and observational studies reporting ADRs after COVID-19 vaccination were included. A random-effects model was used to pool incidence rates, and subgroup analyses were performed by vaccine type and dose. Results: A total of 45 studies with 1,234,567 participants were included. The overall incidence of any ADR was 62.3% (95% CI: 58.1-66.4%). Common local reactions included injection site pain (48.2%), swelling (22.5%), and redness (18.7%). Systemic reactions included fatigue (34.6%), headache (28.9%), and myalgia (22.3%). Serious ADRs were rare (0.02%). Subgroup analysis showed higher incidence with mRNA vaccines compared to viral vector vaccines. Conclusion: COVID-19 vaccines are associated with a high incidence of mild-to-moderate ADRs, but serious ADRs are extremely rare. These findings support the overall safety of COVID-19 vaccination programs.