Understanding the genetic architecture and phenotypic landscape of SPTB gene variants causing hereditary spherocytosis in an Indian cohort.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Human Genetics Pub Date : 2025-06-01 Epub Date: 2025-05-06 DOI:10.1007/s00439-025-02748-8
Tejashree Anil More, Prabhakar Kedar
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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.

了解SPTB基因变异导致遗传性球形红细胞增多症的遗传结构和表型景观在印度队列。
遗传性球形红细胞增多症(HS)是一种常见的溶血性贫血,由编码红细胞膜蛋白的基因缺陷或缺陷引起,如ANK1、SPTB、SLC4A1、EPB42和SPTA1。其中,ANK1和SPTB突变是全球HS最常见的原因。这项研究分析了53名印度HS患者,使用靶向下一代测序(t-NGS)鉴定了33种新的SPTB变体和12种先前报道的SPTB变体。已确定的SPTB变体包括移码(28%)、错义(24%)、无义(44%)和剪接(4%)类型,其中无义变体是最常见的。这些无义变异通常导致蛋白质截断。变异在整个基因中分布广泛,在谱蛋白重复序列和锚蛋白结合区域密度最高,而在四聚域未发现变异。所有鉴定的SPTB变异均表现为杂合遗传,与引起HS的基因的常染色体显性遗传模式一致。然而,一名患者携带复合杂合变异,导致严重贫血,五名患者患有新发SPTB变异。本研究扩展了SPTB变异谱,增强了对谱相关分子缺陷的理解,建立了基因型-表型相关性,并为实验室开发HS基因检测提供了有价值的见解。鉴定出的大量变异突出了像NGS这样的先进技术对HS疾病准确分子诊断的重要性。这种方法不仅支持临床诊断,而且有助于家庭咨询,以改善HS的管理。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
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.
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