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Background <p>Inherited anemias (IA) encompass a diverse group of genetic disorders. While conventional diagnostic tools such as hemoglobin electrophoresis, enzyme assays, and specialized RBC membrane tests identify many cases, a subset of patients remains uncharacterized after exhaustive evaluation. This study aimed to elucidate the genetic basis of such cases using next-generation sequencing (NGS).</p> Methods <p>We retrospectively analyzed 54 patients with unexplained anemia over three years at a single tertiary center in North India. All patients underwent detailed clinical, hematological, and biochemical evaluation, followed by targeted molecular testing. Those who remained undiagnosed were subjected to clinical exome or targeted panel sequencing. Variants were classified according to ACMG guidelines.</p> Results <p>A total of 71 variants were identified, including 27 pathogenic, 19 likely pathogenic, and 25 variants of uncertain significance. Missense mutations predominated (<i>n</i> = 47), followed by splice-site and frameshift changes. Variants were associated with hemoglobinopathies (<i>n</i> = 24), membranopathies (<i>n</i> = 15), enzymopathies (<i>n</i> = 13), congenital dyserythropoietic anemia (<i>n</i> = 10), ADA2 deficiency (<i>n</i> = 3), sitosterolemia (<i>n</i> = 5), and methemoglobinemia (<i>n</i> = 1). Multiple variants were detected in several patients, highlighting genetic complexity. Thalassemias remained the most frequent diagnosis, but hereditary spherocytosis, pyruvate kinase deficiency, and rare syndromes were also well represented.</p> Conclusions <p>Our findings demonstrate that NGS significantly enhances diagnostic yield in uncharacterized IA, uncovering both common and rare pathogenic variants. The spectrum observed underscores the necessity of integrating NGS into routine diagnostic algorithms, particularly in resource-limited settings where conventional assays may be inconclusive. Genotype–phenotype correlation remains essential, especially in cases with multiple or uncertain variants.</p>

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Next-Generation Sequencing Uncovers Wide Genetic Heterogeneity in Uncharacterized Inherited Anemias: Insights from a North Indian Cohort

  • 期刊论文

  • 发表日期：

    2026年5月6日

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  • Ganesh Kumar Viswanathan,
  • Jasmita Dass,
  • Richa Chauhan,
  • Ravi Ranjan,
  • Mukul Aggarwal,
  • Pradeep Kumar,
  • Rishi Dhawan,
  • Tulika Seth,
  • Manoranjan Mahapatra

摘要

Background

Inherited anemias (IA) encompass a diverse group of genetic disorders. While conventional diagnostic tools such as hemoglobin electrophoresis, enzyme assays, and specialized RBC membrane tests identify many cases, a subset of patients remains uncharacterized after exhaustive evaluation. This study aimed to elucidate the genetic basis of such cases using next-generation sequencing (NGS).

Methods

We retrospectively analyzed 54 patients with unexplained anemia over three years at a single tertiary center in North India. All patients underwent detailed clinical, hematological, and biochemical evaluation, followed by targeted molecular testing. Those who remained undiagnosed were subjected to clinical exome or targeted panel sequencing. Variants were classified according to ACMG guidelines.

Results

A total of 71 variants were identified, including 27 pathogenic, 19 likely pathogenic, and 25 variants of uncertain significance. Missense mutations predominated (n = 47), followed by splice-site and frameshift changes. Variants were associated with hemoglobinopathies (n = 24), membranopathies (n = 15), enzymopathies (n = 13), congenital dyserythropoietic anemia (n = 10), ADA2 deficiency (n = 3), sitosterolemia (n = 5), and methemoglobinemia (n = 1). Multiple variants were detected in several patients, highlighting genetic complexity. Thalassemias remained the most frequent diagnosis, but hereditary spherocytosis, pyruvate kinase deficiency, and rare syndromes were also well represented.

Conclusions

Our findings demonstrate that NGS significantly enhances diagnostic yield in uncharacterized IA, uncovering both common and rare pathogenic variants. The spectrum observed underscores the necessity of integrating NGS into routine diagnostic algorithms, particularly in resource-limited settings where conventional assays may be inconclusive. Genotype–phenotype correlation remains essential, especially in cases with multiple or uncertain variants.