Yi Mengni, Wang Yu, Gao Xiaolan, Han Lianshu, Qiu Wenjuan, Gu Xuefan, Maegawa Gustavo H B, Zhang Huiwen
Pediatric Endocrinology and Genetic, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Departments of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA.
J Inherit Metab Dis. 2022 May;45(3):593-604. doi: 10.1002/jimd.12491. Epub 2022 Mar 7.
Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive disorder resulting from the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) caused by pathogenic variants in the GALNS gene. A systematic analysis for genotype-phenotype correlation is essential due to hundreds of variants generating different levels of residual GALNS activity and causing a wide degree of clinical manifestation effects. Here, we retrospectively analyzed clinical and genetic data of 108 unrelated patients with MPS IVA to investigate the variants spectrum of GALNS and assess their clinical effects. In this cohort, 82 patients were classified as severe, 14 as intermediate, and 12 as mild. One hundred and one GALNS variants were identified, of which 47 were novel. Most patients with at least one GALNS null variant were classified as severe phenotype (92%, 33/36). Missense variants mapped to different residues of GALNS protein resulted in different phenotypes in patients with MPS IVA. Ninety-two percent of patients with two missense variants mapped to buried residues were classified as severe (92%, 24/26), while at least one missense variant mapped to surface residues was identified in patients with biallelic missense variants presenting intermediate MPS IVA (78%, 7/9) and presenting mild MPS IVA (86%, 6/7). Our study contributes to a better understanding of the molecular spectrum of GALNS variants and their clinical implications. Based on the data herein reported, we generated a systematic flowchart correlating the GALNS variants to assist in phenotype prediction and classification of patients with MPS IVA.
IVA型黏多糖贮积症（MPS IVA）是一种罕见的常染色体隐性疾病，由GALNS基因的致病变异导致N-乙酰半乳糖胺-6-硫酸酯硫酸酯酶（GALNS）缺乏引起。由于数百种变异产生不同水平的GALNS残余活性并导致广泛程度的临床表现影响，因此对基因型-表型相关性进行系统分析至关重要。在此，我们回顾性分析了108例无关的MPS IVA患者的临床和遗传数据，以研究GALNS的变异谱并评估其临床影响。在该队列中，82例患者被分类为重度，14例为中度，12例为轻度。共鉴定出101种GALNS变异，其中47种是新的。大多数至少有一个GALNS无效变异的患者被分类为重度表型（92%，33/36）。定位到GALNS蛋白不同残基的错义变异在MPS IVA患者中导致不同的表型。92%的有两个错义变异且定位到埋藏残基的患者被分类为重度（92%，24/26），而在双等位基因错义变异表现为中度MPS IVA（78%，7/9）和轻度MPS IVA（86%，6/7）的患者中，至少有一个错义变异定位到表面残基。我们的研究有助于更好地理解GALNS变异的分子谱及其临床意义。基于本文报道的数据，我们生成了一个将GALNS变异相关联的系统流程图，以协助MPS IVA患者的表型预测和分类。
