Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds.

中文翻译：

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荷兰的变色性白细胞营养不良基因型在非高加索地区的患者中发现了新的致病性ARSA变异。

变色性白细胞营养不良（MLD）是一种常染色体隐性遗传性的硫化物贮积病，由溶酶体酶芳基硫酸酯酶A（ASA）的活性不足引起。ARSA基因的遗传分析在MLD诊断和家庭成员筛查中很重要。此外，有关基因型流行的更多信息将有助于解释国家之间的MLD人口差异。在这项研究中，我们确定了患者队列中的31种不同的ARSA变体（n = 67）荷兰MLD专业知识中心。最常见的变体c.1283C> T，p。（Pro428Leu）存在于43位（64％）患者中，并导致荷兰MLD型少年的高患病率（58％）。此外，我们观察到六分之五的非高加索族裔背景患者以前未报告过致病性ARSA变体。总的来说，我们报告了十个新颖的变异，包括四个错义，两个废话，两个移码变异和一个框内插入缺失，它们都被认为是导致计算机疾病的原因。此外，发现一个沉默的变体c.1200C> T，很可能导致错误的外显子剪接，包括部分跳过外显子7。c.1200C> T变体与假缺陷等位基因c.1055A>顺式遗传。 G，p。（Asn352Ser）+ * 96A>G。通过这项研究，我们提供了荷兰独特MLD表型分布的遗传基础。此外，我们的研究证明了遗传分析在MLD诊断中的重要性以及非高加索民族背景患者未报告的病原性ARSA变异的可能性增加。