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Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation
  1. Manu Jamwal1,
  2. Anu Aggarwal1,
  3. Man Updesh Singh Sachdeva1,
  4. Prashant Sharma1,
  5. Pankaj Malhotra2,
  6. Arindam Maitra3,
  7. Reena Das1
  1. 1Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
  2. 2Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
  3. 3National Institute of Biomedical Genomics, Kalyani, West Bengal, India
  1. Correspondence to Professor Reena Das, Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India; reenadaspgi{at}hotmail.com

Abstract

Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the RHAG gene. We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis. Extensive haemolytic work-up including flow cytometry for eosin-5′-maleimide and CD47 expression levels was carried out. Targeted resequencing revealed two probably causative heterozygous mutations in RHAG (Leu336Ser and Ile149Met) and one heterozygous mutation in ANK1 (Glu1046Lys). RHAG involvement was confirmed by decreased RhAG macrocomplex component indicated by the reduced CD47 expression on erythrocytes. In silico analysis concordantly flagged RHAG:Leu336Ser and ANK1:Glu1046Lys as likely deleterious mutation, whereas RHAG:Ile149Met was reported as likely neutral by PROVEAN. Family screening by Sanger sequencing revealed RHAG:Leu336Ser in a mother and ANK1:Glu1046Lys in a father who were both asymptomatic, excluding them as causative dominant events, thus establishing RHAG:Ile149Met, novel de novo mutation as probably causative. This case illustrates the importance of family screening in interpreting next-generation sequencing (NGS) data, as in silico analysis alone can be misleading. Erudite generation of diagnostic possibilities based on a thorough baseline clinical and laboratory work-up remains as important as ever, even as NGS brings about a paradigm shift in the diagnostic work-up of rare haemolytic anaemias.

  • hematopathology
  • haemolytic anaemia

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Footnotes

  • Handling editor Mary Frances McMullin.

  • Contributors MJ, AA, AM, PS and RD designed and performed the experiments, analysed the data and wrote the manuscript. MUSS helped in the flow cytometric analysis. PM was involved in the clinical management of the patient. All authors contributed and approved the final version of the manuscript.

  • Funding This work was supported by institutional funds and Department of Biotechnology, Ministry of Science and Technology, New Delhi (BT/PR12682/MED/12/689/2015). MJ and AA received fellowship from the Indian Council of Medical Research (ICMR), New Delhi.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Institutional Ethics Committee of Post Graduate Institute of Medical Education and Research, Chandigarh, India (vide PGI/IEC/2015/837).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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