背景:β地中海贫血,与HBB突变相关,与血红蛋白A2(HbA2)升高相关,是一种重要的遗传性血红蛋白病,在新加坡发病率和携带者率高。载体筛查对于促进产前咨询和检测至关重要。然而,当HbA2升高的个体没有可识别的HBB疾病相关变异时,他们的后代面临的风险含糊不清。
方法:我们描述了一例HbA2升高的先证者,没有可识别的HBB疾病相关变异,其伴侣是β地中海贫血携带者。通过临床HBB基因测序,多重连接依赖性探针扩增(MLPA)分析,以及所选基因的靶向纳米孔长读数测序,我们对HBB进行了完整的分析,包括启动子区,5UTR和编码基因序列,以及评估潜在的修饰变体和其他罕见的结构变体。
结果:此过程确定先证为KLF1的杂合:c.544T>C(p。Phe182Leu),一种先前已知与良性HbA2水平升高相关的潜在功能多态性。HBB基因座中疾病变体的存在被排除。
结论:这一发现为先证者及其家人提供了清晰的计划生育能力。
BACKGROUND: Beta thalassemia, related to HBB mutation and associated with elevated hemoglobin A2 (HbA2), is an important genetic hemoglobinopathy with high incidences of disease and carrier rates in Singapore. Carrier screening is essential to facilitate prenatal counseling and testing. However, when individuals with elevated HbA2 do not have an identifiable HBB disease-associated variant, there is ambiguity on risk to their offspring.
METHODS: We describe a case report of a proband with elevated HbA2, no identifiable HBB disease-associated variant, whose partner was a beta thalassemia carrier. Through clinical HBB gene sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, as well as targeted Nanopore long read sequencing of selected genes, we performed a complete analysis of HBB including the promoter region, 5\'UTR and coding gene sequence, as well as evaluation for potential modifier variants and other rare structural variants.
RESULTS: This process identified that the proband was heterozygous for KLF1:c.544T>C (p.Phe182Leu), a potential functional polymorphism previously known to be associated with benign elevated HbA2 levels. The presence of disease variants in the HBB locus was excluded.
CONCLUSIONS: This finding provided clarity and enabled family planning for the proband and her family.