{"title":"Understanding the genetic architecture and phenotypic landscape of SPTB gene variants causing hereditary spherocytosis in an Indian cohort.","authors":"Tejashree Anil More, Prabhakar Kedar","doi":"10.1007/s00439-025-02748-8","DOIUrl":null,"url":null,"abstract":"<p><p>Hereditary spherocytosis (HS) is a common form of haemolytic anaemia caused by defects or deficiencies in genes encoding erythrocyte membrane proteins, such as ANK1, SPTB, SLC4A1, EPB42, and SPTA1. Among these, ANK1 and SPTB mutations are the most frequent causes of HS worldwide. This study analysed 53 Indian HS patients, identifying 33 novel and 12 previously reported SPTB variants using targeted next-generation sequencing (t-NGS). The identified SPTB variants included frameshift (28%), missense (24%), nonsense (44%), and splicing (4%) types, with nonsense variants being the most common. These nonsense variants typically result in truncated proteins. The variants were widely distributed across the gene, with the highest density observed in the spectrin repeats and ankyrin-binding domain, while no variants were found in the tetramerization domain. All identified SPTB variants exhibited heterozygous inheritance, consistent with an autosomal dominant inheritance pattern of the gene causing HS. One patient, however, carried compound heterozygous variants, leading to severe anaemia, and five patients had de novo SPTB variants. This study expands the spectrum of SPTB variants, enhances the understanding of spectrin-related molecular defects, establishes genotype-phenotype correlations, and provides valuable insights for laboratories developing genetic tests for HS. The high number of identified variants highlights the importance of advanced technologies like NGS for accurate molecular diagnosis in HS disorder. This approach not only supports clinical diagnostics but also aids in family counseling for improved management of HS.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"633-651"},"PeriodicalIF":3.8000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00439-025-02748-8","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/6 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Hereditary spherocytosis (HS) is a common form of haemolytic anaemia caused by defects or deficiencies in genes encoding erythrocyte membrane proteins, such as ANK1, SPTB, SLC4A1, EPB42, and SPTA1. Among these, ANK1 and SPTB mutations are the most frequent causes of HS worldwide. This study analysed 53 Indian HS patients, identifying 33 novel and 12 previously reported SPTB variants using targeted next-generation sequencing (t-NGS). The identified SPTB variants included frameshift (28%), missense (24%), nonsense (44%), and splicing (4%) types, with nonsense variants being the most common. These nonsense variants typically result in truncated proteins. The variants were widely distributed across the gene, with the highest density observed in the spectrin repeats and ankyrin-binding domain, while no variants were found in the tetramerization domain. All identified SPTB variants exhibited heterozygous inheritance, consistent with an autosomal dominant inheritance pattern of the gene causing HS. One patient, however, carried compound heterozygous variants, leading to severe anaemia, and five patients had de novo SPTB variants. This study expands the spectrum of SPTB variants, enhances the understanding of spectrin-related molecular defects, establishes genotype-phenotype correlations, and provides valuable insights for laboratories developing genetic tests for HS. The high number of identified variants highlights the importance of advanced technologies like NGS for accurate molecular diagnosis in HS disorder. This approach not only supports clinical diagnostics but also aids in family counseling for improved management of HS.
期刊介绍:
Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology.
Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted.
The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.