Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program
Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program
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DOI：
10.1016/j.ymgme.2009.12.014
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发表时间：
2010-04-01
影响因子：
3.8
通讯作者：
Hwu, Wuh-Liang
中科院分区：
文献类型：
--
作者：
Labrousse, Paul;Chien, Yin-Hsiu;Hwu, Wuh-Liang
庞贝氏症是一种由溶酶体酸性α-葡萄糖苷酶（GAA）活性缺乏引起的常染色体隐性溶酶体贮积症（LSD）。这是第一个LSD，其中新生儿筛查已被证明可以改善临床结果。新生儿筛查还在该人群中发现了多种罕见基因变异。在筛查的132，538名新生儿中，对107名干血斑GAA活性低的婴儿（1/1239）进行了基因分型。69名（64.5%）婴儿共有54个突变和35个新的可预测的致病突变：36名（33.6%）没有突变的婴儿是c[17264; 2065 A]假缺陷等位基因纯合子。由于81%的染色体（对照组为14%）为单倍型03，我们发现假缺陷等位基因与其他突变等位基因之间存在联系。筛查发现的庞贝氏症新生儿淋巴细胞GAA活性为0.45 ~ 1.65 nmol/mg/h（正常值66.7 ± 33.8），而100例假阳性病例中仅有2例GAA活性低于2.00 nmol/mg/h（或正常值的3%）。因此，即使在突变杂合性和假性缺陷的人群中，通过基因分型和淋巴细胞GAA测定也可以成功地进行庞贝氏症的新生儿筛查。(C)2009 Elsevier Inc. All rights reserved.
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA) activity. This is the first LSD in which newborn screening has been shown to improve clinical outcomes. Newborn screening also identified multiple rare gene variants in this population. Among 132,538 newborns screened, 107 babies (1 in 1239) who had low dried blood spot GAA activity were genotyped. Sixty-nine (64.5%) babies had a total of 54 mutations and 35 novel predictably pathogenic mutations: 36 babies (33.6%) who had no mutation were homozygous for the c[17264; 2065A] pseudodeficiency allele. Because 81% of the chromosomes (14% in the controls) were in haplotype 03, we found a link between the pseudodeficiency allele and other mutated alleles. The newborns with Pompe disease detected by screening had lymphocyte GAA activities 0.45 to 1.65 nmol/mg/h (normal 66.7 +/- 33.8), while only 2 of the 100 false-positive cases had GAA activity less than 2.00 nmol/mg/h (or 3% of the normal mean). Therefore, newborn screening for Pompe disease could be successfully conducted by including genotyping and lymphocyte GAA assay, even in a population with mutation heterozygosity and pseudodeficiency. (C) 2009 Elsevier Inc. All rights reserved.