Improvement in the sensitivity of newborn screening for Fabry disease among females through the use of a high-throughput and cost-effective method, DNA mass spectrometry

Lu, Yung Hsiu; Huang, Po Hsun; Wang, Li Yun; Hsu, Ting-Rong; Li, Hsing Yuan; Lee, Pi Chang; Hsieh, Yu Ping; Hung, Sheng-Che; Wang, Yu Chen; Chang, Sheng Kai; Lee, Ya Ting; Ho, Ping; Ho, Hui Chen; Niu, Dau Ming

doi:10.1038/s10038-017-0366-y

Cited by 18 publications

(22 citation statements)

References 31 publications

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“…Although we used a higher cutoff <80% of median α-Gal A activity, false-negative ndings may have been obtained among the female FD patients herein. Additional tests, such as blood Lyso-Gb3 assays [43], hotspot mutation screening [44], or even whole GLA gene sequencing, may improve the rate of false-negative results. Most patients with FD in Taiwan harbor variants out of a pool of only 21 pathogenic mutations [45].…”

Section: Discussionmentioning

confidence: 99%

Fabry disease screening in high-risk populations in Japan: A nationwide study

Yoshida

Kido

Sawada

et al. 2020

Preprint

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Background: Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in the deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause multisystemic dysfunction. A recent screening study among neonates reported an increase in the incidence of FD, and numerous FD patients remain undiagnosed or even misdiagnosed . Therefore, this study aimed to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all prefectures in Japan . A total of 601 hospitals participated in this study. Results: Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were identified from among 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment. Conclusions: From among 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.

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Section: Discussionmentioning

confidence: 99%

Fabry disease screening in high-risk populations in Japan: A nationwide study

Yoshida

Kido

Sawada

et al. 2020

Preprint

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“…Although we used a higher cutoff <80% of median α-Gal A activity, it is undeniable that there may be falsenegative female patients with FD. Additional tests, such as blood Lyso-Gb3 assays [42], hotspot mutation screening [43], or even whole GLA gene sequencing, may improve the false-negative rate.…”

Section: Discussionmentioning

confidence: 99%

Fabry disease screening in high-risk populations in Japan: A nationwide study

Yoshida

Kido

Sawada

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Fabry disease (FD) is a X-linked inherited disorder caused by mutations in the GLA gene, which results in deficiency of α-galactosidase A (α-Gal A). This leads to the progressive accumulation of metabolites, which can cause malfunctions in systemic organs. A recent screening study in newborns showed that the incidence of FD was more frequent than previously estimated and that there are still many undiagnosed or misdiagnosed patients with FD. Therefore, the purpose of this study was to identify patients with FD by performing high-risk screening in 18,135 individuals, enrolled from October 2006 to March 2019, with renal, cardiac, or neurological manifestations from all of the prefectures in Japan. A total of 601 hospitals participated in this study.Results: Low α-Gal A activity was detected in 846 individuals, with 224 of them diagnosed with FD by GLA sequencing. Cases with a family history of FD (n = 64) were also subjected to sequencing, without α-Gal A assay, as per individual request, and 12 of them were diagnosed with a variant of FD. A total of 236 patients with FD (97 males and 139 females) were detected from the 18,199 participants. A total of 101 GLA variants, including 26 novel variants, were detected in the 236 patients with FD from 143 families, with 39 amenable variants (39%) and 79 of the 236 patients (33%) suitable for migalastat treatment.Conclusions: From the 18,199 participants, 101 GLA variants, including 26 novel variants, were identified in the 236 patients with FD from 143 families. Migalastat was identified as a suitable treatment option in 33% of the patients with FD and 39% of the GLA variants were detected as amenable. Therefore, the simple screening protocol using dried blood spots that was performed in this study could be useful for early diagnosis and selection of appropriate treatments for FD in high-risk and underdiagnosed patients with various renal, cardiac, or neurological manifestations.

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“…Moreover, many quality reference materials such as gender and SNPs can be built in for sample traceability. Furthermore, the Agena iPLEX SMA assay has great adaptability with DBS specimens, and previous studies have demonstrated the successful use of Agena iPLEX assay for Fabry NBS (Lu et al, 2018). Last but not least, the Agena iPLEX SMA assay has the advantage of flexibility in that more diseases can be incorporated into the current assay, such as integrated severe combined immunodeficiency, the first DNA-based NBS condition that was detected by measuring the T-cell receptor excision circles, for prospective molecular screening.…”

Section: Discussionmentioning

confidence: 99%

Newborn Screening for Spinal Muscular Atrophy in China Using DNA Mass Spectrometry

Lin

Lin²,

Yin³

et al. 2019

Front. Genet.

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Background: Spinal muscular atrophy (SMA) is the most common neurodegenerative disorder and the leading genetic cause of infant mortality. Early detection of SMA through newborn screening (NBS) is essential to selecting pre-symptomatic treatment and ensuring optimal outcome, as well as, prompting the urgent need for effective screening methods. This study aimed to determine the feasibility of applying an Agena iPLEX SMA assay in NBS for SMA in China. Methods: We developed an Agena iPLEX SMA assay based on the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and evaluated the performance of this assay through assessment of 167 previously-genotyped samples. Then we conducted a pilot study to apply this assay for SMA NBS. The SMN1 and SMN2 copy number of screen-positive patients were determined by multiplex ligation-dependent probe amplification analysis. Results: The sensitivity and specificity of the Agena iPLEX SMA assay were both 100%. Three patients with homozygous SMN1 deletion were successfully identified and conformed by multiplex ligation-dependent probe amplification analysis. Two patients had two SMN2 copies, which was correlated with severe SMA type I phenotype; both of them exhibited neurogenic lesion and with decreased muscle power. Another patient with four SMN2 copies, whose genotype correlated with milder SMA type III or IV phenotype, had normal growth and development without clinical symptoms. Conclusions: The Agena iPLEX SMA assay is an effective and reliable approach for population-based SMA NBS. The first large-scale pilot study using this assay in the Mainland of China showed that large-scale implementation of population-based NBS for SMA is feasible.

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Improvement in the sensitivity of newborn screening for Fabry disease among females through the use of a high-throughput and cost-effective method, DNA mass spectrometry

Cited by 18 publications

References 31 publications

Fabry disease screening in high-risk populations in Japan: A nationwide study

Fabry disease screening in high-risk populations in Japan: A nationwide study

Fabry disease screening in high-risk populations in Japan: A nationwide study

Newborn Screening for Spinal Muscular Atrophy in China Using DNA Mass Spectrometry

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