title: GLA variation p.E66Q identified as the genetic etiology of Fabry disease using exome sequencing.
abstract: Fabry disease (FD) was an X-linked lysosomal storage disorder resulting from a deficiency in glycosphingolipid catabolism caused by mutations in the α-galactosidase A gene GLA. Variant FD patients did not present with classical symptoms during childhood and were undiagnosed or misdiagnosed with other kidney diseases, such as chronic glomerulonephritis (CGN). In this study, we utilized exome sequencing and Sanger sequencing identified the variation p.E66Q of GLA completely co-segregated with the disease phenotype in a Chinese family, which previously been diagnosed as possible CGN. Female patients exhibited preferential X-chromosome inactivation (XCI) of the normal p.E66 allele, as indicated by XCI analysis. By measuring α-Gal A activity, we found that male patients in the pedigree had just little enzymatic activity while female patients had residual enzymatic activity. These patients were diagnosed with renal variant FD in subsequent clinical review. Our results directly implicated the GLA mutation p.E66Q as the genetic etiology of the Chinese renal variant FD pedigree.
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Peng
authors.affiliation: The Reproductive Medicine Hospital of the First Hospital of Lanzhou University, Lanzhou, Gansu, China. Electronic address: xiaojuanyanwu@163.com.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lusi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Reproductive Medicine Hospital of the First Hospital of Lanzhou University, Lanzhou, Gansu, China.
authors.forename: Xuehong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Hexiang
authors.initials: H
authors.lastname: Peng
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Sanchuan
authors.initials: S
authors.lastname: Luo
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Xia
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China.
authors.forename: Jiada
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Yao
authors.affiliation: The State Key Laboratory of Medical Genetics and School of Life Science, Central South University, Changsha, Hunan, China. Electronic address: huzhengmao@sklmg.edu.cn.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People; D059472:Exome; D000795:Fabry Disease / Q000201:enzymology / Q000235:genetics*; D005190:Family; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: Exome sequencing; Fabry disease; The GLA gene; XCI analysis; p.E66Q