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Updated: Jan 6, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
The application of next-generation sequencing technology in congenital haemolytic anaemia: a systematic review and
1Blood Transfusion Department, The Seventh Affiliated Hospital, Sun Yat-Sen University, No. 628, Zhenyuan Road, Xinhu Street, Guangming District, Shenzhen City, 518107, Guangdong Province, China.
Insights
Next-generation sequencing (NGS) effectively diagnoses congenital hemolytic anemia (CHA), identifying genetic causes in nearly half of all patients. This advanced genetic testing shows higher success rates in familial cases and specific anemia subtypes, supporting its use in clinical practice.
Area of Science:
- Hematology
- Genetics
- Medical Diagnostics
Background:
- Congenital hemolytic anemia (CHA) presents significant diagnostic challenges due to its genetic complexity.
- Current diagnostic approaches often struggle to identify the underlying genetic cause of CHA.
Purpose of the Study:
- To systematically review and meta-analyze the diagnostic efficacy of next-generation sequencing (NGS) for congenital hemolytic anemia (CHA).
- To evaluate the performance of NGS across different CHA subtypes and patient demographics.
Main Methods:
- Systematic literature search of PubMed and Web of Science databases until April 2025.
- Inclusion of studies utilizing NGS techniques (WES, WGS, CES, targeted panels) in CHA patients.
- Random-effects meta-analysis to calculate pooled positive detection rates and confidence intervals, with subgroup analyses.
Main Results:
- The pooled positive detection rate for NGS in CHA was 44.3% (95% CI: 32.4-56.3%).
- Detection rates were significantly higher in patients with a family history (51.0%) compared to sporadic cases (16.9%).
- Red cell membrane disorders showed the highest diagnostic yield (45.3%), with SPTB, ANK1, and SPTA1 being key genes.
Conclusions:
- NGS offers substantial diagnostic utility for CHA, resolving nearly half of cases and over 50% of familial presentations.
- The findings support the integration of NGS into first-line CHA diagnostics, particularly targeted gene panels for cost-effectiveness.
- Specific gene mutations (SPTB, PKLR, ANK1, SLC4A1, SPTA1) are frequently identified, aiding in diagnosis and understanding disease mechanisms.
Abstract:
Congenital haemolytic anaemia (CHA) poses diagnostic challenges due to genetic heterogeneity. This systematic review and meta-analysis evaluates the diagnostic efficacy of next-generation sequencing (NGS) in CHA. We systematically searched PubMed and Web of Science until April 2025. Inclusion criteria encompassed studies applying NGS (whole-exome sequencing [WES], whole-genome sequencing [WGS], clinical exome sequencing [CES], or targeted panels) in confirmed/suspected CHA patients. Pooled positive detection rates with 95% confidence intervals (CIs) were calculated using a random-effects model. Subgroup analyses stratified by family history and disease subtypes were performed. Study quality was assessed via modified STARD criteria. Ten studies involving 885 patients were included. The pooled positive detection rate of NGS was 44.3% (95% CI: 32.4-56.3%, p < 0.001). Subgroup analysis revealed significantly higher detection rates in patients with family history (51.0%; 95% CI: 32.8-69.2%) versus sporadic cases (16.9%; 95% CI: 8.4-27.2%, p < 0.001). Disease-specific yields varied: red cell membrane disorders showed the highest rate (45.3%; 95% CI: 35.2-55.7%), followed by enzymatic disorders (26.7%; 95% CI: 18.8-35.3%). Among all positive cases, pathogenic variants in five core genes accounted for 76.82% of detected mutations: SPTB (25.06%), PKLR (17.10%), ANK1 (11.94%), SLC4A1 (11.48%), and SPTA1 (11.24%). SPTB and ANK1 mutations were most frequently identified in red cell membrane disorders, while PKLR variants were exclusive to enzymatic disorders. NGS demonstrates substantial diagnostic utility in CHA, resolving nearly half of cases overall and over 50% of familial presentations. Its efficacy is particularly pronounced in red cell membrane disorders linked to cytoskeletal genes (SPTB, ANK1, SPTA1). These findings support integrating NGS into first-line CHA diagnostics, with prioritization of core gene panels for cost-effective implementation.
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