A novel heterozygous mutation in ANK1 solves a mystery of a patient with hyperbilirubinemia and splenomegaly.

Patients presented with jaundice and splenomegaly are easily diagnosed as having liver diseases. Actually, some atypical cases belong to hemolytic diseases leading to secondary hemochromatosis, which is easily misdiagnosed or never diagnosed. Here, we describe an atypical case in a 27 years old man presenting with unconjugated hyperbilirubinemia and splenomegaly since early childhood, who was hospitalized to check for any possible causes related to liver diseases. However, the probable etiology related to hemolytic diseases and liver disease was ruled out by negative traditional tests, which left a mystery to us. Fortunately, next-generation sequencing is becoming a suitable choice to determine the candidate genes responsible for rare or inherited disorders. A novel de novo mutation (c.5032delA) was firstly identified through whole exome sequencing which could induce an arginine to glycine substitution at residue 1678 (p.R1678Gfs*12), causing a premature termination codon in exon 38 of ANK1. ANK1 is involved in erythrocyte cytoskeleton formation, and contributes to one of the most common causes of hereditary spherocytosis (HS). Besides, homology-modeling analysis confirmed the loss-of-function of frameshift variant of ANK1 with bioinformatics methods. This work adds new knowledge in the etiology of hereditary spherocytosis. In addition, genetic testing can open up new perspectives for atypical and unknown diseases when traditional tests cannot be met.