Pan Yinghong, Sniderman King Lisa, Vengoechea Elizabeth, Liu Ruby, Chen-Deutsch Xiangwen, Smith Sara, Wang Yuanyuan, da Silva Cristina, Chakraborty Polly, Kallu Eshawnvie, Nallamilli Babi Ramesh Reddy, Donti Taraka, Walter Angela, Kazemi Sean, Hegde Madhuri
Revvity Omics, Pittsburgh, PA, USA.
Sanofi, Cambridge, MA, USA.
Mol Genet Metab. 2025 May;145(1):109082. doi: 10.1016/j.ymgme.2025.109082. Epub 2025 Mar 15.
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A (α-Gal A) due to pathogenic variants of the GLA gene. This study reports findings from data collected through The Lantern Project, including results from α-Gal A enzyme activity and globotriaosylsphingosine (lyso-Gb3) biomarker assays from dried blood spots, as well as next-generation sequencing (NGS). A total of 513 enzyme tests, 284 lyso-Gb3 tests, and 994 NGS tests were conducted on 1380 individuals (708 female, 661 male, 11 sex unknown) with clinical suspicion, or family history or abnormal newborn screening (NBS) results who participated in the project from December 2018-April 2023. Among these individuals, 21 % (103 male and 2 sex unknown) had abnormal α-Gal A levels (range 0.054-1.069 μM/h, normal level ≥ 1.10 μM/h), and 70 % (79 female, 115 male and 2 sex unknown) had elevated lyso-Gb3 levels (range 1.12-130.56 ng/mL, normal level ≤ 1.11 ng/mL). A total of 137 different reportable variants have been identified in this cohort including novel variants c.[351T>G;361G>C] (p.I117M;A121P), c.370-558_370-1del, c.548del, and c.1165C>T (p.P389S). All female patients with loss-of-function (LOF) variants and biomarker results were found to have elevated lyso-Gb3 levels. In contrast to those with LOF variants, females with missense GLA variants had various lyso-Gb3 results. Pathogenic (P)/likely pathogenic (LP) missense variants [including c.1087C>T (p.R363C), c.1088G>A (p.R363H), c.593T>C (p.I198T), c.644A>G (p.N215S), c.335G>A (p.R112H), c.337T>C (p.F113L), and c.835C>G (p.Q279E)] were identified in 16 female patients with normal lyso-Gb3 levels. These findings suggest that the use of lyso-Gb3 testing without GLA sequencing may result in missed diagnosis in some female patients with FD missense variants. Different biochemical and DNA variant profiles have been observed between NBS and non-NBS male patients. Among the non-NBS males, both enzyme and biomarker results correlate with age at the time of testing, which appear to be an approximated indicator for age of onset and disease severity. Among all the NBS males with both enzyme and lyso-Gb3 results, abnormal α-Gal A levels were found in all having P/LP variants except for the 11 who had c.427G>A (p.A143T) or c.870G>C (p.M290I), while normal lyso-Gb3 results have been found in many males with various P/LP variants - though it should of course be noted that lyso-Gb3 levels may increase over time. Our observation in NBS male patients may suggest that the enzyme test has a higher sensitivity, while lyso-Gb3 test has a higher specificity, and when combined with DNA test results, can provide a more comprehensive and reliable result. This manuscript presents the largest-to-date, comprehensive, multi-testing Fabry cohort with demographic information and biochemical phenotypes from a single clinical laboratory. The results from this dataset demonstrate that the integration of enzyme, biomarker, and NGS testing can enhance screening/diagnostic efficiency for FD, particularly for female patients.
法布里病（FD）是一种X连锁溶酶体贮积症，由GLA基因的致病变异导致α-半乳糖苷酶A（α-Gal A）缺乏引起。本研究报告了通过“灯笼计划”收集的数据结果，包括来自干血斑的α-Gal A酶活性和球三糖神经酰胺（溶酶体Gb3）生物标志物检测结果，以及下一代测序（NGS）结果。对2018年12月至2023年4月参与该项目的1380名个体（708名女性、661名男性、11名性别未知）进行了总共513次酶检测、284次溶酶体Gb3检测和994次NGS检测，这些个体有临床疑似症状、家族病史或新生儿筛查（NBS）结果异常。在这些个体中，21%（103名男性和2名性别未知）的α-Gal A水平异常（范围为0.054 - 1.069 μM/h，正常水平≥1.10 μM/h），70%（79名女性、115名男性和2名性别未知）的溶酶体Gb3水平升高（范围为1.12 - 130.56 ng/mL，正常水平≤1.11 ng/mL）。在该队列中总共鉴定出137种不同的可报告变异，包括新变异c.[351T>G;361G>C]（p.I117M;A121P）、c.370 - 558_370 - 1del、c.548del和c.1165C>T（p.P389S）。所有具有功能丧失（LOF）变异和生物标志物结果的女性患者均发现溶酶体Gb3水平升高。与具有LOF变异的女性不同（的是），具有错义GLA变异的女性有各种溶酶体Gb3结果。在16名溶酶体Gb3水平正常的女性患者中鉴定出致病性（P）/可能致病性（LP）错义变异[包括c.1087C>T（p.R363C）、c.1088G>A（p.R363H）、c.593T>C（p.I198T）、c.644A>G（p.N215S）、c.335G>A（p.R112H）、c.337T>C（p.F113L）和c.835C>G（p.Q279E）]。这些发现表明，在未进行GLA测序的情况下使用溶酶体Gb3检测可能会导致一些患有FD错义变异的女性患者漏诊。在NBS男性患者和非NBS男性患者之间观察到了不同的生化和DNA变异谱。在非NBS男性中，酶和生物标志物结果均与检测时的年龄相关，这似乎是发病年龄和疾病严重程度的一个近似指标。在所有同时有酶和溶酶体Gb3结果的NBS男性中，除了11名具有c.427G>A（p.A143T）或c.870G>C（p.M290I）的男性外，所有具有P/LP变异的男性均发现α-Gal A水平异常，而在许多具有各种P/LP变异的男性中发现溶酶体Gb3结果正常——当然应该注意到溶酶体Gb3水平可能会随时间增加。我们在NBS男性患者中的观察结果可能表明，酶检测具有更高的敏感性，而溶酶体Gb3检测具有更高的特异性，并且与DNA检测结果相结合时，可以提供更全面和可靠的结果。本手稿展示了来自单个临床实验室的、包含人口统计学信息和生化表型的、迄今为止最大的、全面的、多检测法布里病队列。该数据集的结果表明，酶、生物标志物和NGS检测的整合可以提高FD的筛查/诊断效率，特别是对于女性患者。
