Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Eur J Med Genet. 2022 Mar;65(3):104447. doi: 10.1016/j.ejmg.2022.104447. Epub 2022 Feb 8.
MPS II is an X linked recessive lysosomal storage disorder with multi-system involvement and marked molecular heterogeneity. In this study, we explored the clinical and molecular spectrum of 144 Indian patients with MPS II from 130 unrelated families. Clinical information was collected on a predesigned clinical proforma. Sanger method was employed to sequence all the exons and exon/intron boundaries of the IDS gene. In cases where causative variation was not detected by Sanger sequencing, MLPA and RFLP were performed to identify large deletions/duplications and complex rearrangements. Cytogenetic microarray was done in one patient to see the breakpoints and extent of deletion. In one patient with no detectable likely pathogenic or pathogenic variation, whole-genome sequencing was also performed. Novel variants were systematically assessed by in silico prediction software and protein modelling. The pathogenicity of variants was established based on ACMG criteria. An attempt was also made to establish a genotype-phenotype correlation. Positive family history was present in 31% (41/130) of patients. Developmental delay and intellectual disability were the main reasons for referral. Macrocephaly, coarse facies and dysostosis were present in almost all patients. Hepatosplenomegaly, joint contractures and short stature were the characteristic features, seen in 87% (101/116), 67.8% (74/109) and 41.4% (41/99) patients respectively. Attenuated phenotype was seen in 32.6% (47/144) patients, while severe phenotype was seen in 63% (91/144) patients. The detection rate for likely pathogenic or pathogenic variants in our cohort is 95.5% (107/112) by Sanger sequencing, MLPA and RFLP. We also found two variants of unknown significance, one each by Sanger sequencing and WGS. Total of 71 variants were identified by Sanger sequencing and 29 of these variants were found to be novel. Amongst the novel variants, there was a considerable proportion (51%) of frameshift variants (15/29). Almost half of the causative variants were located in exon 3,8 and 9. A significant genotype-phenotype correlation was also noted for both known and novel variants. This information about the genotype spectrum and phenotype will be helpful for diagnostic and prognostic purposes.
MPS II 是一种 X 连锁隐性溶酶体贮积症，涉及多系统，具有明显的分子异质性。在这项研究中，我们从 130 个无关家庭中探索了 144 名印度 MPS II 患者的临床和分子谱。临床信息是在预先设计的临床方案上收集的。采用 Sanger 法对 IDS 基因的所有外显子和外显子/内含子边界进行测序。在 Sanger 测序未检测到致病变异的情况下，进行 MLPA 和 RFLP 以鉴定大片段缺失/重复和复杂重排。对一名患者进行细胞遗传学微阵列分析以确定缺失的断点和范围。在一名未检测到可能的致病性或致病性变异的患者中，还进行了全基因组测序。通过计算预测软件和蛋白质建模系统地评估新变体。根据 ACMG 标准确定变体的致病性。还试图建立基因型-表型相关性。
阳性家族史见于 31%（41/130）的患者。发育迟缓及智力残疾是就诊的主要原因。几乎所有患者均存在大头畸形、面容粗糙和骨发育不良。肝脾肿大、关节挛缩和身材矮小是其特征性表现，分别见于 87%（101/116）、67.8%（74/109）和 41.4%（41/99）的患者。32.6%（47/144）的患者表现为轻度表型，63%（91/144）的患者表现为重度表型。通过 Sanger 测序、MLPA 和 RFLP，我们在队列中检测到可能的致病性或致病性变异的检出率为 95.5%（107/112）。我们还发现了两个意义不明的变异，分别通过 Sanger 测序和 WGS 发现。通过 Sanger 测序共发现 71 个变异，其中 29 个为新变异。在新变异中，有相当一部分（51%）为移码变异（15/29）。约一半的致病变异位于外显子 3、8 和 9。对于已知和新变异，也观察到了显著的基因型-表型相关性。
关于基因型谱和表型的这些信息将有助于诊断和预后目的。
