LOVD–DASH: A comprehensive LOVD database coupled with diagnosis and an at‐risk assessment system for hemoglobinopathies

Zhang, Li; Zhang, Qianqian; Tang, Yaohua; Cong, Peikuan; Ye, Yuhua; Chen, Shiping; Zhang, Xinhua; Chen, Yan; Zhu, Baosheng; Cai, Wei; Chen, Shaoke; Cai, Ren; Guo, Xiaoling; Zhang, Chonglin; Zhou, Yuqiu; Zou, Jie; Liu, Yan‐Hui; Chen, Biyan; Yan, Shanhuo; Chen, Yajun; Zhou, Yuehong; Ding, Hongmei; Li, Xiarong; Chen, Dianyu; Zhong, Jianmei; Shang, Xuan; Liu, Xuanzhu; Qi, Ming; Xu, Xiang

doi:10.1002/humu.23863

Cited by 11 publications

(8 citation statements)

References 32 publications

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“…For example, rs67385638, rs11036474 and rs10128556 were more strongly associated with HbF levels than rs7482144. Conditional analysis showed that rs11036474 and rs10128556 were the most independently-associated variants found in the HbF-1 and HbF-2 subgroups while rs11036474 has not been reported in other populations except in China [ 28 ]; our findings on rs10128556 corroborate those of Galarneu et al [ 6 ].…”

Section: Discussionsupporting

confidence: 88%

Unique Polymorphisms at BCL11A, HBS1L-MYB and HBB Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease

Akbulut-Jeradi¹,

Fernandez²,

Khaldi³

et al. 2021

JPM

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Patients with sickle cell disease (SCD) in Kuwait have elevated HbF levels ranging from ~10–44%; however, the modulating factors are unclear. We investigated the association of single nucleotide polymorphisms (SNPs) at BCL11A, HBS1L-MYB and HBB with HbF levels in 237 Kuwaiti SCD patients, divided into 3 subgroups according to their HbF levels. Illumina Ampliseq custom DNA panel was used for genotyping and confirmed by arrayed primer extension or Sanger sequencing. In the BCL11A locus, the CC genotype of rs7606173 [χ2 = 16.5] and (GG) of rs10195871 [χ2 = 15.0] were associated with Hb-F1 and HbF-2 subgroups, unlike rs1427404-T [χ2 = 17.3], which showed the highest association across the three subgroups. HBS1L-MYB locus revealed 2 previously-described SNPs (rs66650371 [χ2 = 9.5] and rs35795442 [χ2 = 9.2]) and 2 previously-unreported SNPs, (rs13220662 [χ2 = 6.2] and rs1406811 [χ2 = 6.7]) that were associated with the HbF-3 subgroup, making this the key locus elevating HbF to the highest levels. HBB cluster variants were associated with lower levels of HbF (β = −1.1). We report four previously-unpublished variants showing significant association with HbF. Each of the three quantitative trait loci affects HbF levels differently; unique SNPs, especially in HBS1L-MYB, elevate HbF to the highest levels.

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Section: Discussionsupporting

confidence: 88%

Unique Polymorphisms at BCL11A, HBS1L-MYB and HBB Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease

Akbulut-Jeradi¹,

Fernandez²,

Khaldi³

et al. 2021

JPM

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“…The test we developed is focused on the Southern Chinese population where there are 46 common variants. Based on the positioning of the targeting primers, we suggest that the current test should be able to detect any of the known 290 pathogenic variants 16 . However, to improve the accuracy for the detection of rarer HBB variants located in the 5′ proximal and 3′ distal regions as well those deep within intron 2, it will be necessary to use additional targeting primers, positioned to avoid common SNPs.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the positioning of the targeting primers, we suggest that the current test should be able to detect any of the known 290 pathogenic variants. 16 However, to improve the accuracy for the detection of rarer HBB variants located in the 5 0 proximal and 3 0 distal regions as well those deep within intron 2, it will be necessary to use additional targeting primers, positioned to avoid common SNPs. We estimate that in addition to the nine targeted primers used in this version of the assay, a minimum of a further three inverse primer pairs would be needed to guarantee full mutation coverage of the entire HBB gene.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

“…13,14 Since the first database for globin gene variants was established in 2002, 15 there are now 924 HBB variants recorded in worldwide populations (https://lovd.bx.psu.edu). 16 Among these 924 variants, 290 are classified as pathogenic and mainly include single nucleotide variants and indels as well as a few rare gene deletions. In a recent detailed study of over 10 000 Southern Chinese couples, 17 targeted next-generation sequencing identified 46 different HBB pathogenic variants with six accounting for more than 95% of all b-thalassaemia cases; c.126_129delCTTT (CD41-42), c.316-197C>T (IVS-II-654), c.-78A>G (À28), c.52A>T (CD17), c.79G>A (CD26),and c.216_217insA (CD71-72).…”

Section: Introductionmentioning

confidence: 99%

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Noninvasive prenatal diagnosis for pregnancies at risk for β‐thalassaemia: a retrospective study

Linpeng

et al. 2020

BJOG

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Objective To evaluate the clinical feasibility of noninvasive prenatal diagnosis (NIPD) for b-thalassaemia using circulating single molecule amplification and re-sequencing technology (cSMART). Design zThrough carrier screening, 102 pregnant Chinese couples carrying pathogenic HBB gene variants were recruited to the study. Pregnancies were managed using traditional invasive prenatal diagnosis (IPD). Retrospectively, we evaluated the archived pregnancy plasma DNA by NIPD to evaluate the performance of our cSMART assay for fetal genotyping. Setting Chinese prenatal diagnostic centres specialising in thalassaemia testing. Population Chinese carrier couples at high genetic risk for bthalassaemia. Methods Fetal cell sampling was performed by amniocentesis and HBB genotypes were determined by reverse dot blot. NIPD was performed by a newly designed HBB cSMART assay and fetal genotypes were called by measuring the allelic ratios in the maternal cell-free DNA. Main outcome measures Concordance of HBB fetal genotyping between IPD and NIPD and the sensitivity and specificity of NIPD. Results Invasive prenatal diagnosis identified 29 affected homozygotes or compound heterozygotes, 54 heterozygotes and 19 normal homozygotes. Compared with IPD results, 99 of 102 fetuses (97%) were correctly genotyped by our NIPD assay. Two of three discordant samples were false positives and the other sample involved an incorrect call of a heterozygote carrier as a homozygote normal. Overall, the sensitivity and specificity of our NIPD assay was 100% (95% CI 88.06-100.00%) and 97.26% (95% CI 90.45-99.67%), respectively. Conclusions This study demonstrates that our cSMART-based NIPD assay for b-thalassaemia has potential clinical utility as an alternative to IPD for pregnant HBB carrier couples.

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“…Eleven types of β-globin gene cluster deletions have been reported in the Chinese (Fig. 1 .1-A, Table 1 ) 5 – 10 . Coinheritance of these deletions with other β-thalassemias or Hb variants results in phenotypes ranging from asymptomatic to β-thalassemias major 11 .…”

Section: Introductionmentioning

confidence: 99%

Establishment and application of a novel method based on single nucleotide polymorphism analysis for detecting β-globin gene cluster deletions

Zhan

Wang

et al. 2020

Sci Rep

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β-Globin gene mutations reduce or terminate the production of beta globin chains, of which approximately 10% are large deletions within the β-globin gene cluster. Because gene deletion leads to loss of heterozygosity at single nucleotide polymorphism (SNP), a novel method for detecting β-globin gene cluster deletions based on SNP heterozygosity analysis was established in this study. The location range of SNPs was selected according to the breakpoint of β-globin gene cluster deletions. SNPs were screened using bioinformatics analysis and population sequencing data. A novel method which enables genotyping of multiplex SNPs based on tetra-primer ARMS-PCR was designed and optimized. Forty clinical samples were tested in parallel by this method and MLPA to verify the performance of this method for detecting β-globin gene cluster deletion. Six informative SNPs were obtained, achieving heterozygote coverage of 93.3% in normal individuals. Genotyping of six SNPs were successfully integrated into two multiplex tetra-primer ARMS-PCR reactions. The sensitivity, specificity, positive predictive value and negative predictive value of the method for detecting β-globin gene cluster deletion were 100%, 96.30%, 92.86%, and 100%, respectively. This is a simple, cost-effective and novel method for detecting β-globin gene cluster deletions, which may be suitable for use in combination with MLPA for thalassemia molecular testing.

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LOVD–DASH: A comprehensive LOVD database coupled with diagnosis and an at‐risk assessment system for hemoglobinopathies

Cited by 11 publications

References 32 publications

Unique Polymorphisms at BCL11A, HBS1L-MYB and HBB Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease

Unique Polymorphisms at BCL11A, HBS1L-MYB and HBB Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease

Noninvasive prenatal diagnosis for pregnancies at risk for β‐thalassaemia: a retrospective study

Establishment and application of a novel method based on single nucleotide polymorphism analysis for detecting β-globin gene cluster deletions

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