Rapid Identification of Biallelic SPTB Mutation in a Neonate with Severe Congenital Hemolytic Anemia and Liver Failure

Richmond, Christopher M.; Campbell, Sally; Foo, Hee W.; Lunke, Sebastian; Stark, Zornitza; Moody, Amanda; Bannister, Elizabeth; Greenway, Anthea; Brown, Natasha

doi:10.1159/000505886

Cited by 12Erythrocyte Function and PathophysiologyHemoglobinopathies and Related DisordersGenomics and Rare Diseases

Rapid Identification of Biallelic SPTB Mutation in a Neonate with Severe Congenital Hemolytic Anemia and Liver Failure

Open access

Richmond, Christopher M., Campbell, Sally, Foo, Hee W., Lunke, Sebastian, Stark, Zornitza, Moody, Amanda, Bannister, Elizabeth, Greenway, Anthea +1 more·2020·Molecular Syndromology

DOI 10.1159/000505886PMC PMC7109415

Open this paper in CoChat — free account

Abstract

Heterozygous pathogenic variants in SPTB cause autosomal dominant hereditary spherocytosis, an important cause of neonatal nonimmune hemolytic anemia. Biallelic mutations are rarely reported, all with severe neonatal presentation. We describe rapid (68 h) genomic diagnosis of homozygous β-spectrin deficiency in a newborn with severe transfusion-dependent hemolytic anemia, conjugated hyperbilirubinemia, and progressive liver failure. Trio whole-exome sequencing identified a novel biallelic SPTB variant (c.6119C>T; p.Thr2040Ile) located in the critical spectrin repeat region. Pretransfusion blood film showed marked spherocytosis including microspherocytes and nucleated erythrocytes, and eosin-5-maleimide (E5M) staining was markedly reduced, supporting pathogenicity. Both asymptomatic heterozygous parents demonstrated mildly reduced E5M staining, with occasional spherocytes and elliptocytes. Early molecular diagnosis facilitated hypertransfusion to suppress ineffective erythropoiesis and reverse hepatic dysfunction. This report broadens the genotypic and phenotypic spectrum of spectrin deficiency and highlights the utility of rapid genomic testing in facilitating early diagnosis and informing targeted therapy in critically ill patients.

Integrity signals

Registry

Crossref · 10.1159/000505886

Cites

24 of 24 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Rapid RNA studies confirmed the pathogenicity of a homozygous splice-site ASNS variant within 10 days, and 2 other variants of uncertain significance were reclassified as likely pathogenic after further phenotyping over 6 months.
“Rapid RNA studies confirmed the pathogenicity of a homozygous splicesite ASNS variant in 10 days, and 2 other variants of uncertain significance were reclassified as likely pathogenic after further phenotyping during a period of 6 months.22”
From Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System (2020) · cites this paper as [22]

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594 · see citing works
A global reference for human genetic variation
The 1000 Genomes Project Consortium, authors, C., Auton, A., Abecasis, G. R., Steering committee, Altshuler, D. M., Durbin, R. M., Abecasis, G. R., Bentley, D. R., Chakravarti, A., et al. (2015) · Nature · doi:10.1038/nature15393 · Cited by 18,247 · see citing works
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm
Kumar, P., Henikoff, S., & Ng, P. C. (2009) · Nature Protocols · doi:10.1038/nprot.2009.86 · Cited by 6,521 · see citing works
MutationTaster2: mutation prediction for the deep-sequencing age
Schwarz, J. M., Cooper, D. N., Schuelke, M., & Seelow, D. (2014) · Nature Methods · doi:10.1038/nmeth.2890 · Cited by 3,652 · see citing works
The mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2019) · doi:10.1101/531210 · Cited by 1,662 · see citing works
Hereditary spherocytosis
Perrotta, S., Gallagher, P. G., & Mohandas, N. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61588-3 · Cited by 620 · see citing works
Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization
Farnaes, L., Hildreth, A., Sweeney, N. M., Clark, M. M., Chowdhury, S., Nahas, S., Cakici, J. A., Benson, W., Kaplan, R. H., Kronick, R., et al. (2018) · npj Genomic Medicine · doi:10.1038/s41525-018-0049-4 · Cited by 445 · see citing works
Meeting the challenges of implementing rapid genomic testing in acute pediatric care.
Stark, Z., Lunke, S., Brett, G. R., Tan, N. B., Stapleton, R., Kumble, S., Yeung, A., Phelan, D. G., Chong, B., Fanjul-Fernandez, M., et al. (2018) · Genetics in Medicine · doi:10.1038/gim.2018.37 · Cited by 159 · see citing works
Self-citation
Neonatal management and outcome in alloimmune hemolytic disease
Ree, I. M. C., Smits‐Wintjens, V. E. H. J., van der Bom, J. G., van Klink, J. M. M., Oepkes, D., & Lopriore, E. (2017) · Expert Review of Hematology · doi:10.1080/17474086.2017.1331124 · Cited by 134 · see citing works
Clinical utility of next‐generation sequencing in the diagnosis of hereditary haemolytic anaemias
Agarwal, A. M., Nussenzveig, R. H., Reading, N. S., Patel, J. L., Sangle, N. A., Salama, M. E., Prchal, J. T., Perkins, S. L., Yaish, H. M., & Christensen, R. D. (2016) · British Journal of Haematology · doi:10.1111/bjh.14131 · Cited by 97 · see citing works
Causes of hemolysis in neonates with extreme hyperbilirubinemia
Christensen, R. D., Nussenzveig, R. H., Yaish, H. M., Henry, E., Eggert, L. D., & Agarwal, A. M. (2014) · Journal of Perinatology · doi:10.1038/jp.2014.68 · Cited by 84 · see citing works
Recurrent fatal hydrops fetalis associated with a nucleotide substitution in the erythrocyte beta-spectrin gene.
Gallagher, P. G., Weed, S. A., Tse, W. T., Benoit, L., Morrow, J. S., Marchesi, S. L., Mohandas, N., & Forget, B. G. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117766 · Cited by 72 · see citing works
Deficiency of alpha-spectrin synthesis in burst-forming units-erythroid in lethal hereditary spherocytosis
Whitfield, C., Follweiler, J., Lopresti‐Morrow, L., & Miller, B. (1991) · Blood · doi:10.1182/blood.v78.11.3043.3043 · Cited by 60 · see citing works
Mutation of a highly conserved residue of betaI spectrin associated with fatal and near-fatal neonatal hemolytic anemia.
Gallagher, P. G., Petruzzi, M. J., Weed, S. A., Zhang, Z., Marchesi, S. L., Mohandas, N., Morrow, J. S., & Forget, B. G. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119155 · Cited by 51 · see citing works
Evaluating eosin-5-maleimide binding as a diagnostic test for hereditary spherocytosis in newborn infants
Christensen, R. D., Agarwal, A. M., Nussenzveig, R. H., Heikal, N., Liew, M. A., & Yaish, H. M. (2014) · Journal of Perinatology · doi:10.1038/jp.2014.202 · Cited by 29 · see citing works
Pyruvate kinase deficiency associated with severe liver dysfunction in the newborn
Raphaël, M. F., van Wijk, R., Schweizer, J. J., Meeteren, N. S.-V., Kindermann, A., van Solinge, W. W., & Smiers, F. J. W. (2007) · American Journal of Hematology · doi:10.1002/ajh.20942 · Cited by 28 · see citing works
Direct Hyperbilirubinemia Complicating ABO Hemolytic Disease of the Newborn
Sivan, Y., Merlob, P., Nutman, J., & Reisner, S. H. (1983) · Clinical Pediatrics · doi:10.1177/000992288302200802 · Cited by 22 · see citing works
Hereditary spherocytosis in the elderly
Friedman, E., Williams, J. C., & van Hook, L. (1988) · The American Journal of Medicine · doi:10.1016/0002-9343(88)90275-6 · Cited by 19 · see citing works
Novel α-Spectrin Mutation in Trans with α-SpectrinLEPRA Causing Severe Neonatal Jaundice from Hereditary Spherocytosis
Nussenzveig, R. H., Christensen, R. D., Prchal, J. T., Yaish, H. M., & Agarwal, A. M. (2014) · Neonatology · doi:10.1159/000365586 · Cited by 18 · see citing works
Coinheritance of hereditary spherocytosis and reversibility of cirrhosis in a young female patient with hereditary hemochromatosis
Höblinger, A., Erdmann, C., Straßburg, C., Sauerbruch, T., & Lammert, F. (2009) · European journal of medical research · doi:10.1186/2047-783x-14-4-182 · Cited by 11 · see citing works
Excessive Bilirubin Elevation in a Patient with Hereditary Spherocytosis and Intrahepatic Cholestasis
Wree, A., Canbay, A. E., Müller-Beißenhirtz, H., Dechêne, A., Gerken, G., Dührsen, U., Lammert, F., & Nückel, H. (2011) · Zeitschrift für Gastroenterologie · doi:10.1055/s-0031-1273368 · Cited by 5 · see citing works
The Clinical Utility Of Next-Generation Sequencing In The Diagnosis Of Hereditary Hemolytic Anemias
Nussenzveig, R. H., Sangle, N. A., Christensen, R. D., Salama, M. E., Prchal, J. T., Yaish, H. M., & Agarwal, A. M. (2013) · Blood · doi:10.1182/blood.v122.21.3421.3421 · Cited by 4 · see citing works

Flagged first, then by citations

Sorted by citations

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System
Australian Genomics Health Alliance Acute Care Flagship, Lunke, S., Eggers, S., Wilson, M., Patel, C., Barnett, C. P., Pinner, J., Sandaradura, S. A., Buckley, M. F., Krzesinski, E. I., et al. (2020) · JAMA · doi:10.1001/jama.2020.7671 · Cited by 239 · see citing works
Self-citation
Whole‐exome sequencing uncovered genetic diagnosis of severe inherited haemolytic anaemia: Correlation with clinical phenotypes
Songdej, D., Kadegasem, P., Tangbubpha, N., Sasanakul, W., Deelertthaweesap, B., Chuansumrit, A., & Sirachainan, N. (2022) · British Journal of Haematology · doi:10.1111/bjh.18356 · Cited by 18 · see citing works
Hemolytic-Pred: A machine learning-based predictor for hemolytic proteins using position and composition-based features
Perveen, G., Alturise, F., Alkhalifah, T., & Khan, Y. D. (2023) · Digital Health · doi:10.1177/20552076231180739 · Cited by 18 · see citing works
Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved
Mezzi, N., Messaoud, O., Mkaouar, R., Zitouna, N., Romdhane, S., Abdessalem, G., Charfeddine, C., Mâazoul, F., Ourteni, I., Hamdi, Y., et al. (2021) · Genes · doi:10.3390/genes12111820 · Cited by 15 · see citing works
Genetic aetiologies of acute liver failure
Hegarty, R., & Thompson, R. J. (2024) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12733 · Cited by 7 · see citing works
Hereditary Spherocytosis With Liver Transplantation After Cirrhosis: A Case Report
Yang, X., Wang, W. J., Fan, W., Cai, L., Ye, F., Lin, S., & Liu, X. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.823724 · Cited by 7 · see citing works
Current Status of Molecular Diagnosis of Hereditary Hemolytic Anemia in Korea
Chueh, H. W., Shim, Y. J., Jung, H. L., Kim, N., Hwang, S. M., Kim, M., Choi, H. S., & on behalf of the Red Blood Cell Disorder Working Party of the Korean Society of Hematology (2024) · Journal of Korean Medical Science · doi:10.3346/jkms.2024.39.e162 · Cited by 4 · see citing works
Integrative preimplantation genetic testing analysis for a Chinese family with hereditary spherocytosis caused by a novel splicing variant of SPTB
Tian, Y., Wang, Y., Yang, H. J., Gao, P., Xu, H., Wu, Y., Li, M., Chen, H., Daru, L., & Yan, H. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1221853 · Cited by 2 · see citing works
Complications of delayed diagnosis and challenges: successfully managed SPTB gene variant hereditary spherocytosis with hepatocellular jaundice—a case report
Mekonnen, S., Adefris, D., Aki, B. S., Wotiye, A. B., Azmeraw, D., Kassa, T., Teshome, E., & Farris, H. (2024) · Journal of Medical Case Reports · doi:10.1186/s13256-024-04872-x · Cited by 2 · see citing works
Whole exome sequencing identifies a novel SPTB frameshift mutation causing hereditary spherocytosis in the Chinese population
Liu, X.-D., Yang, K., Xiao, J., Huang, H., Zhang, X., & Huang, J. (2022) · Annals of Hematology · doi:10.1007/s00277-022-04900-0 · Cited by 2 · see citing works
Genetic Mutations of Congenital Red Cell Membrane Defects in Hydrops Fetalis
Komwilaisak, P., Wichajarn, K., Jaruk, C., Komwilaisak, R., Sirachainan, N., Laoaroon, N., Jirapradittha, J., Paopongsawan, P., Kiatchoosakun, P., & Suwannaying, K. (2025) · Fetal Diagnosis and Therapy · doi:10.1159/000548041 · Cited by 1 · see citing works
Atypical Course of Hereditary Spherocytic Anemia With Severely Elevated Liver Enzymes
Banadyha, N. V., & Komorovsky, R. (2023) · Indian Pediatrics · doi:10.1007/s13312-023-2867-1 · Cited by 1 · see citing works

A novel SPTB gene mutation in neonatal hereditary spherocytosis: A case report
Liu, Y., Zheng, J., Li, S., Fang, Y., Sun, C., Li, N., Liu, G., & Shu, J. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9062 · Cited by 10 · see citing works
A novel SPTB gene mutation in neonatal hereditary spherocytosis: a case report and literature reviewPreprint
Liu, Y., Li, S., Shu, J., Fang, Y., Sun, C., Li, N., & Liu, G. (2019) · Research Square · doi:10.21203/rs.2.10866/v1
Three Novel Spectrin Variants in Jaundiced Neonates
Christensen, R. D., Agarwal, A. M., Yaish, H. M., Reading, N. S., O’Brien, E. A., & Prchal, J. T. (2017) · Clinical Pediatrics · doi:10.1177/0009922816687326 · Cited by 4 · see citing works
Hereditary Spherocytosis Due to a Novel Variant, P.Q1034X, in the Beta Subunit of the Spectrin Gene
Afridi, F. A., van Helmond, J. L., Ahmed, R., & Ganesh, J. (2020) · Blood · doi:10.1182/blood-2020-134681
Precise diagnosis of a hereditary spherocytosis patient with complicated hematological phenotype
Liang, G., Lin, Z., Zhang, Y., Zhang, Q., Zhu, D., Liang, X., Xie, H., Wei, X., & Shang, X. (2024) · Molecular Genetics and Genomics · doi:10.1007/s00438-024-02150-5 · Cited by 2 · see citing works

Authors: Richmond, C. M., Campbell, S., Foo, H. W., Lunke, S., Stark, Z., Moody, A., Bannister, E., Greenway, A., & Brown, N.
Affiliations: Griffith University (AU)
Royal Children's Hospital (AU)
The University of Melbourne (AU)
ORCID: Richmond, Christopher M.
Campbell, Sally
Foo, Hee W.
Lunke, Sebastian
Stark, Zornitza
Bannister, Elizabeth
Brown, Natasha
Venue: Molecular Syndromology
Publisher: S. Karger AG
Published: 2020
Volume: 11
Issue: 1
Pages: 50-55
ISSN: 1661-8769 (ISSN-L)
1661-8777
DOI: 10.1159/000505886
PMC: PMC7109415
OpenAlex: W3004002986
Cited by: 12
References: 24
Citations by year: 2025: 1 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 1
FWCI: 1.20
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.karger.com/Services/SiteLicenses (vor)
www.karger.com/Services/SiteLicenses (tdm)
Locations: Molecular Syndromology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Griffith Research Online (submittedVersion, other-oa)
Topics: Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords: SPTB, biallelic variants, hereditary spherocytosis, congenital hemolytic anemia, neonatal liver failure, conjugated hyperbilirubinemia, novel variants, hypertransfusion, trio exome sequencing

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Rapid Identification of Biallelic SPTB Mutation in a Neonate with Severe Congenital Hemolytic Anemia and Liver Failure

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks