Complex heterozygous mutations in hereditary spherocytosis:A case report

BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to promote the application of gene detection technology in children with HS,with the goals of identifying more related gene mutations,supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children,and providing important guidance for the diagnosis,treatment,and prevention of HS in children.CASE SUMMARY A 1-year and 5-month-old patient presented jaundice during the neonatal period,mild anemia 8 months later,splenic enlargement at 1 year and 5 months,and brittle red blood cell permeability.Genetic testing was performed on the patient,their parents,and sister.Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1.Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother.Combined with the clinical symptoms of the children,it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause,providing important guidance for revealing the pathogenesis,diagnosis,treatment,and promotion of gene detection technology in children with HS.CONCLUSION This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1,which provides a reference for exploring HS.

Clinical manifestations of adult hereditary spherocytosis with novel SPTB gene mutations and hyperjaundice:A case report

BACKGROUND The aim of the present study was to enhance understanding of the diagnosis and treatment of atypical hereditary spherocytosis(HS),and to broaden the diagnostic thoughts of physicians for patients with jaundice.CASE SUMMARY A 28-year-old male presented with jaundice,bile duct stone,and splenomegaly,but without anemia.Other causes of jaundice were excluded,and gene se-quencing revealed a novel heterozygous variant of c.1801C>T(p.Q601X)in exon 14 of the SPTB(NM_01355436)gene on chromosome 14(chr14:65260580)in the patient’s blood;the biological parents and child of the patient did not have similar variants.A splenectomy was performed on the patient and his bilirubin levels returned to normal after surgery.Thus,a novel gene variant causing HS was identified.This variant may result in the truncation ofβ-hemoglobin in the erythrocyte membrane,leading to loss of normal function,jaundice,and hemolytic anemia.The clinical manifestations of the patient were hyperjaundice and an absence of typical hemolysis during the course of the disease,which caused challenges for diagnosis by the clinicians.CONCLUSION Following a definitive diagnosis,genetic testing and response to treatment identified a gene variant site for a novel hemolytic anemia.

Gilbert’s syndrome coexisting with hereditary spherocytosis might not be rare: Six case reports

BACKGROUND Both Gilbert's syndrome(GS)and hereditary spherocytosis(HS)are common genetic disorders.However,comorbidity of GS with HS has always been considered a rare phenomenon,and it can impede accurate diagnoses in the presence of isolated unconjugated hyperbilirubinemia.CASE SUMMARY In a study on Levitt’s carbon monoxide(CO)breath test for the differential diagnosis of isolated hyperbilirubinemia,we found six GS patients with HS in 6 mo.The patients,including five males and one female,aged 25-58 years,were from four families and generally in good health.Their chronic fluctuating jaundice and/or hyperbilirubinemia had been diagnosed as simple constitutional jaundice for 6-30 years.Liver function tests showed isolated unconjugated hyperbilirubinemia with serum total bilirubin ranging from 20.7-75.4μmol/L.Blood hemoglobin was normal in five cases,and slightly decreased in one(11.5 g/dL).Overt hemolytic signs were absent,while erythrocyte lifespan determined by the newly developed Levitt’s CO breath test was significantly short(15-50 d),definitely demonstrating the presence of hemolysis.Given that their unconjugated hyperbilirubinemia compared inappropriately with hemolytic severity,as indicated by the hemoglobin level,further combined genetic tests for both UGT1A1 and hereditary erythrocyte deficiencies were conducted.These tests confirmed,at last,the coexistence of GS with HS.CONCLUSION Comorbidity of GS and HS might not be uncommon in isolated unconjugated hyperbilirubinemia.While CO breath test would sensitively detect the hemolysis,the discordance between the hyperbilirubinemia and hemoglobin level could strongly indicate the coexistence of GS and HS.

Severe hyperbilirubinemia in a neonate with hereditary spherocytosis due to a de novo ankyrin mutation: A case report

BACKGROUND Hereditary spherocytosis(HS)is a common type of hemolytic anemia caused by a red cell membrane disorder.HS type 1(HS1)is mostly caused by mutations in ankyrin(ANK1).Newborns with HS1 usually only exhibit anemia and mild jaundice.We herein report a case of HS1 and discuss its clinical characteristics.CASE SUMMARY A 2-d-old male full-term newborn was admitted to our hospital with severe,intractable neonatal jaundice.Laboratory investigations showed hemolytic anemia and hyperbilirubinemia and excluded immune-mediated hemolysis.The patient underwent two exchange transfusions and one plasmapheresis resulting in significantly reduced serum bilirubin.Hematologic analyses and genomic DNA sequencing studies were performed.The trio clinical exome sequencing revealed a de novo null heterozygous mutation in the patient's ANK1 gene:c.841C>T(p.Arg281Ter).This mutation results in the premature termination of the ANK1 protein.CONCLUSION Our case demonstrates that genetic analysis can be an essential method for diagnosing HS when a newborn has severe hyperbilirubinemia.

Targeted next-generation sequencing identifies a novel nonsense mutation in ANK1 for hereditary spherocytosis:A case report

BACKGROUND Hereditary spherocytosis(HS)is characterized by anemia,jaundice,splenomegaly,and cholelithiasis,and is caused by abnormal genes encoding red blood cell membrane components.The most common mutations found in HS are in the ANK1 gene.CASE SUMMARY A 4-mo-old girl was admitted to our hospital with pallor that had lasted for more than 2 mo.She presented with jaundice,anemia and splenomegaly.A heterozygous mutation of ANK1(exon23:c.G2467T:p.E823X)was identified,and the mutation was determined to be autosomal dominant.This mutation is linked to the relatively serious anemia she had after birth;this anemia improved with age.CONCLUSION The utilization of next-generation sequencing may assist with the accurate diagnosis of HS,especially in atypical cases.

Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis

Hereditary spherocytosis （HS）, the most common cause of congenital hemolytic anemia, is caused by deficiency of the ery- throcyte membrane proteins. Five causative genes （ANK1, SPTB, SPTA1, SLC4AI, and EPB42） have been identified. To date, molecular genetic studies have been performed in different populations, including the American, European, Brazilian, Japanese and Korean populations, whereas only a few studies have been described in the Chinese population. Here, by reanalysis of the exome data, we revealed causative mutations and established a definitive diagnosis of HS in all 38 Chinese families. We found 34 novel mutations and four reported mutations in three known HS-causing genes--17 in ANK1, 17 in SPTB and four in SLC4A1, suggesting that ANK1 and SPTB are the major genes in Chinese patients with HS. All of the ANK1 or SPTB mutations, scattered throughout the entire genes, are non-recurrent; and most of them are null mutations, which might cause HS via a hap-loinsufficiency mechanism. De novo mutations in ANK1 or SPTB often occur with an unexpected high frequency （87.5% and 64.2%, respectively）. Our study updates our knowledge about the genetic profile of HS in Chinese and shows that family-based, especially parent-offspring trio, sequencing analysis can help to increase the diagnostic power and improve diagnostic efficiency.

Allo-hematopoietic stem cell transplantation is a potential treatment for a patient with a combined disorder of hereditary spherocytosis

Both human hereditary spherocytosis （HS） and chronic myelogenous leukemia （CML） are life threatening. Herein we have reported the case of a woman with a combined disorder of HS and CML who underwent the matched sibling allogeneic stem cell transplantation. The complete donor erythroid cells were obtained. The red blood cell counts significantly improved throughout life comparing with pre-hematopoietic stem cell transplantation （HSCT）. Reticulocyte counts normalized, and BCR-ABL was cleared away. The total bilirubin level was also corrected in this recipient. Our case is a rare example with a combined disorder of HS and CML following allogeneic stem cell transplantation. HS was not a contraindication for patient in the matched sibling transplant setting.