BACKGROUND Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms. RESULTS We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls. CONCLUSION The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.

中文翻译：

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干血斑中GLA变体与α-半乳糖苷酶A谱之间的相关性：对巴西患者的一项观察性研究。

背景技术法布里病是由α-半乳糖苷酶A缺乏引起的罕见的X连锁遗传病。已经描述了GLA基因中的数百种突变和非编码单倍型。然而，许多变体的意义不明，这引发了对诊断和治疗的怀疑。干血斑（DBS）样品中的α-半乳糖苷酶A酶活性被广泛用于筛查目的。但是，即使找到低于正常值的值，也需要进行新的测试以确认诊断。在这里，我们描述了在具有法布里病症状的大量巴西人口中对GLA变体及其与DBSα-半乳糖苷酶A酶活性的相关性的分析。结果我们通过DNA测序分析了803名疑似法布里病或属于高危人群的男性患者的GLA变异。在179个人中，检测到58种不同的外显子变体。从中，有50种被描述为致病性变体，有8种被描述为未知意义的变体。其他个体表现出复杂的非编码单倍型或没有变异。有趣的是，DBS中的酶促活性在致病性变体和其他基因型之间有所不同，包括重要性不明的变体。第一个代表平均剩余活性的12％，而其他代表的水平高于健康对照者的70％。结论与存在未知病原体，非编码单倍型或无变异体的受试者相比，具有已知病原体变异体的雄性大鼠DBS中α-半乳糖苷酶A的活性显着降低，表明这些基因型可能具有非致病性。这些发现使人们更好地了解了DBS样品中α-半乳糖苷酶A的生化结果，以及非编码单倍型和GLA基因中未知意义的变体的潜在非致病性。这些结果无疑将有助于临床医生决定对携带导致这种罕见但危及生命的疾病的基因变异的患者进行治疗。