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Mol Genet Metab. 2018 Feb;123(2):140-147. doi: 10.1016/j.ymgme.2017.06.002. Epub 2017 Jun 8.

Functional and biological studies of α-galactosidase A variants with uncertain significance from newborn screening in Taiwan.

Author information

1
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Chinese Foundation of Health, Newborn Screening Center, Taipei, Taiwan.
2
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
3
Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
4
Chinese Foundation of Health, Newborn Screening Center, Taipei, Taiwan.
5
Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
6
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: dmniu@vghtpe.gov.tw.
7
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan; Department of Pediatrics, Taipei City Hospital, Renai Branch, Taipei, Taiwan. Electronic address: yjchen@ym.edu.tw.

Abstract

Fabry disease is an X-linked disorder resulted from deficiency of α-galactosidase A (GLA) activity. In Taiwan, a total of 792,247 newborns were screened from 2008 to 2014 in two newborn screening centers, and 13 variants of uncertain significance (VOUS) in the GLA gene were identified. To determine whether these variants were pathogenic or not, functional, biochemical, clinical and pedigree analyses were performed. In vitro functional assay was established through site-directed mutagenesis, and four in silico tools were used to predict pathogenesis. The enzyme activity of dried blood spots and plasma metabolite lyso-Gb3 level from subjects with the variants were measured. Additionally, clinical manifestations were evaluated extensively from the subjects and their relatives. Our results revealed that p.G104V, p.I232T, p.D322H, and p.G360C all exhibited relatively low residual enzyme activities and elevated plasma lyso-Gb3 level. These data strongly suggest that these Fabry mutations may cause classical or later-onset phenotypes. In contrast, neither significantly clinical symptoms nor elevated lyso-Gb3 level was found in cases with p.P60S, p.A108T, p.S304T, p.R356Q, and p.P362T variants, which may be non-pathogenic or milder forms of Fabry variants. More data need to be included for the patients with p.N53D, p.P210S, p.M296L, and p.K391T variants. The established system provides us more information to classify these GLA variants.

KEYWORDS:

Alpha-galactosidase; Fabry disease; Lyso-Gb3; Newborn screening; Variants of uncertain significance

PMID:
28615118
DOI:
10.1016/j.ymgme.2017.06.002
[Indexed for MEDLINE]

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