RT Journal Article
SR Electronic
T1 Overhydrated stomatocytosis associated with a complex <em>RHAG</em> genotype including a novel <em>de novo</em> mutation
JF Journal of Clinical Pathology
JO J Clin Pathol
FD BMJ Publishing Group Ltd and Association of Clinical Pathologists
SP 648
OP 652
DO 10.1136/jclinpath-2018-205018
VO 71
IS 7
A1 Jamwal, Manu
A1 Aggarwal, Anu
A1 Sachdeva, Man Updesh Singh
A1 Sharma, Prashant
A1 Malhotra, Pankaj
A1 Maitra, Arindam
A1 Das, Reena
YR 2018
UL http://jcp.bmj.com/content/71/7/648.abstract
AB 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.