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Background <p>Congenital dyserythropoietic anaemia type I (CDA-I) is a rare inherited bone marrow failure syndrome characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts. CDA-I is primarily caused by biallelic pathogenic variants in <i>CDAN1</i>, while mutations in <i>C15ORF41</i> account for a much rarer subtype, classified as CDA-Ib. Reports of <i>C15ORF41</i>-associated CDA-I from the Indian population are extremely limited.</p> Methods <p>We investigated a transfusion-dependent male child presenting with neonatal jaundice and persistent <b>anaemia</b>. Hematological evaluation and bone marrow examination were performed to assess erythroid morphology. Targeted next-generation sequencing (NGS) was used to identify potential pathogenic variants in genes associated with congenital <b>anaemia</b>. Variant validation and segregation analysis were carried out by Sanger sequencing. In silico pathogenicity prediction tools and structural modeling were applied to assess the functional impact of the identified variant.</p> Results <p>Bone marrow examination revealed erythroid hyperplasia with marked dyserythropoietic features consistent with CDA. Targeted NGS identified a novel homozygous missense variant in <i>C15ORF41</i> (c.251T &gt; A; p.Val84Glu), while no pathogenic variants were detected in <i>CDAN1</i>. Sanger sequencing confirmed heterozygous carrier status in both parents, supporting autosomal recessive inheritance. The variant was absent from major population databases and predicted to be deleterious by multiple computational tools. Structural modeling indicated that the substitution may destabilize the conserved N-terminal domain of the <i>C15ORF41</i> protein. According to ACMG guidelines, the variant was classified as likely pathogenic.</p> Conclusion <p>This report describes a novel homozygous <i>C15ORF41</i> variant causing CDA-Ib in an Indian patient. The finding expands the mutational and ethnic spectrum of CDA-I and underscores the value of early molecular diagnosis in patients with unexplained congenital anemia for accurate classification, genetic counseling, and clinical management.</p>

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A novel homozygous C15ORF41 variant (c.251T > A; p.Val84Glu) causing congenital dyserythropoietic anemia type Ib in an Indian patient: molecular and structural evidence

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Prachi Kamble,
  • Rashmi Dongerdiye,
  • Tejashree More,
  • Arati Saptarshi,
  • Prashant Warang,
  • Girish Subramaniam,
  • Manisha Madkaikar,
  • Prabhakar S. Kedar

摘要

Background

Congenital dyserythropoietic anaemia type I (CDA-I) is a rare inherited bone marrow failure syndrome characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts. CDA-I is primarily caused by biallelic pathogenic variants in CDAN1, while mutations in C15ORF41 account for a much rarer subtype, classified as CDA-Ib. Reports of C15ORF41-associated CDA-I from the Indian population are extremely limited.

Methods

We investigated a transfusion-dependent male child presenting with neonatal jaundice and persistent anaemia. Hematological evaluation and bone marrow examination were performed to assess erythroid morphology. Targeted next-generation sequencing (NGS) was used to identify potential pathogenic variants in genes associated with congenital anaemia. Variant validation and segregation analysis were carried out by Sanger sequencing. In silico pathogenicity prediction tools and structural modeling were applied to assess the functional impact of the identified variant.

Results

Bone marrow examination revealed erythroid hyperplasia with marked dyserythropoietic features consistent with CDA. Targeted NGS identified a novel homozygous missense variant in C15ORF41 (c.251T > A; p.Val84Glu), while no pathogenic variants were detected in CDAN1. Sanger sequencing confirmed heterozygous carrier status in both parents, supporting autosomal recessive inheritance. The variant was absent from major population databases and predicted to be deleterious by multiple computational tools. Structural modeling indicated that the substitution may destabilize the conserved N-terminal domain of the C15ORF41 protein. According to ACMG guidelines, the variant was classified as likely pathogenic.

Conclusion

This report describes a novel homozygous C15ORF41 variant causing CDA-Ib in an Indian patient. The finding expands the mutational and ethnic spectrum of CDA-I and underscores the value of early molecular diagnosis in patients with unexplained congenital anemia for accurate classification, genetic counseling, and clinical management.