简介:粘多糖是一组溶酶体贮积症,包括七种类型,根据被破坏的酶进行分类。这些酶的功能失调导致糖胺聚糖(GAG)在各种组织中的积累。由于遗传和临床异质性,诊断和区分不同类型是具有挑战性的。遗传方法如全外显子组测序(WES)和Sanger测序是检测患者致病变异的准确方法。方法:32例粘多糖贮积症,主要来自有近亲婚姻的家庭,进行了基因检查。在这些中,14例接受了靶向测序,而其余的则接受了WES。分析了WES的结果,并使用生物信息学工具检查了变体的致病性。此外,进行了家庭内部的隔离分析。结果:在大多数情况下,检测到致病性或可能的致病性变异。在已知的IDS中检测到16种先前报道的变体和6种新变体(c.458G>C,c.701del,c.920T>G),GNS(c.1430A>T),GALNS(c.1218_1221dup),和SGSH(c.149T>C)基因。此外,我们首次在三个纯合子患者中发现了NAGLU基因的c.259G>C替换。这种取代以前被报道为杂合的。除了与IDS基因相关的变异,半合子,所有其他变体都是纯合的。讨论:看来,正在研究的家庭中近亲结婚的高比率对这种疾病的发生产生了重大影响。总的来说,这些发现可以扩大粘多糖中致病变异的范围。遗传方法,尤其是WES,非常准确,可以单独使用或与其他诊断方法结合使用,以更精确和快速地诊断粘多糖病。此外,它们可能有利于家庭筛查和疾病预防。
Introduction: Mucopolysaccharidoses are a group of lysosomal storage disorders that include seven types that are classified based on the enzymes that are disrupted. Malfunction of these enzymes leads to the accumulation of glycosaminoglycans (GAGs) in various tissues. Due to genetic and clinical heterogeneity, diagnosing and distinguishing the different types is challenging. Genetic methods such as whole exome sequencing (WES) and Sanger sequencing are accurate methods for detecting pathogenic variants in patients. Methods: Thirty-two cases of mucopolysaccharidosis, predominantly from families with consanguineous marriages, were genetically examined. Out of these, fourteen cases underwent targeted sequencing, while the rest underwent WES. The results of WES were analyzed and the pathogenicity of the variants was examined using bioinformatics tools. In addition, a segregation analysis within families was carried out. Results: In most cases, a pathogenic or likely pathogenic variant was detected. Sixteen previously reported variants and six new variants were detected in the known IDS (c.458G>C, c.701del, c.920T>G), GNS (c.1430A>T), GALNS (c.1218_1221dup), and SGSH (c.149T>C) genes. Furthermore, we discovered a c.259G>C substitution in the NAGLU gene for the first time in three homozygous patients. This substitution was previously reported as heterozygous. Except for the variants related to the IDS gene, which were hemizygous, all the other variants were homozygous. Discussion: It appears that the high rate of consanguineous marriages in the families being studied has had a significant impact on the occurrence of this disease. Overall, these findings could expand the spectrum of pathogenic variants in mucopolysaccharidoses. Genetic methods, especially WES, are very accurate and can be used alone or in conjunction with other diagnostic methods for a more precise and rapid diagnosis of mucopolysaccharidoses. Additionally, they could be beneficial for family screening and disease prevention.