Intrafamilial Phenotypic Variability among Siblings with an Identical Variant in the ANK1 gene Causing Hereditary Spherocytosis – A Report of Two Siblings
C. Hari Prasath, P. Indira, P. Anil Kumar, Pentala SripoojaAbstract
Background:
Hereditary spherocytosis (HS) shows considerable phenotypic variability even among individuals harboring identical pathogenic variants, with intrafamilial differences remaining under-recognized in clinical practice. We report two siblings with an identical heterozygous
Clinical Description:
A 9-year-old, previously asymptomatic girl, born out of a third-degree consanguineous marriage, presented with an abrupt onset of yellowish discoloration of skin and urine, following a transient febrile illness. Family history was unremarkable. Examination revealed normal anthropometry and stable vitals, with severe pallor, icterus, and hepatosplenomegaly.
Management and Outcome:
Investigations showed hemoglobin 5.5 g/dL, reticulocyte count 15%, total bilirubin 4.2 mg/dL, with Coombs-negative hemolysis and microspherocytosis on peripheral smear. Liver enzymes, infective work-up for hepatitis, hemoglobin electrophoresis, and glucose-6-phosphate dehydrogenase were within normal limits. Osmotic fragility was increased. Investigations on the 7-year-old asymptomatic younger sibling showed hemoglobin 10.8 g/dL, borderline reticulocytosis, and mildly increased osmotic fragility. On whole exome sequencing, both siblings were found to have a heterozygous, likely pathogenic frameshift variant (NM_020476.3:c. 617del; p.Gly206AspfsTer47) in the
Conclusion:
Children with HS may remain asymptomatic for years, and members within the same family with identical variant may present with varying phenotypes. A high degree of suspicion and systematic work-up for unexplained anemia, along with genetic analysis, can help reach a diagnosis.