Ghaffari Saeed R, Rafati Maryam, Shadnoush Mahdi, Pourbabaee Shokooh, Aghighi Mohammad, Mirab Samiee Siamak, Kermanchi Jamshid, Alaei Mohammad R, Salehpour Shadab, Amirkashani Davoud, Setoodeh Aria, Sarkhail Peymaneh, Badv Reza Shervin, Aminzadeh Majid, Shiva Siamak, Eshraghi Peyman, Moravej Hossein, Hashemipour Mahin, Rostampour Noushin, Hamidieh Amir Ali, Shamsian Bibi Shahin, Shams Sedigheh, Zamanfar Daniel, Ebrahimi Ayoub, Otadi Ali, Tara Seyedeh Zahra, Barati Zeinab, Fakhri Laya, Hoseini Azadeh, Amiri Hosna, Ramandi Somayeh, Mostofinezhad Niusha, Kani Zahra Pahlevani, Mohammadyari Elham, Khosravi Mahsa, Saadati Masoome, Hoseininasab Fatemeh, Khorram Khorshid Hamid Reza, Modaberisaber Younes
Department of Genomics, Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran.
Department of Reproductive genetics, Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
Hum Mutat. 2022 Apr;43(4):e1-e23. doi: 10.1002/humu.24328. Epub 2022 Feb 3.
Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.
黏多糖贮积症（MPSs）是一类罕见的、异质性的先天性代谢缺陷病（IEM），通过临床、生化和基因检测相结合的方式进行诊断。本研究的目的是对伊朗最大规模的MPS患者队列（来自289个无关家庭的302名患者）进行分子特征分析，并追踪他们的种族和地理来源。对289名患者中的185名使用了针对IEM的二代测序（NGS）面板，随后进行补充性的桑格测序，这使得154名MPS患者和5名非MPS的IEM得到诊断（诊断率：85.9%）。此外，106名有阳性结果的转诊患者接受了重新分析和确认性检测，其中104名确诊为MPS。在总共258名MPS患者中，225名是纯合子，90名携带新变异，9名有拷贝数变异。MPS IV是最常见的类型（34.8%），其次是MPS I（22.7%）和MPS VI（22.5%）。地理来源分析揭示了ARSB（c.430G>A、c.962T>C [p.Leu321Pro]、c.281C>A [p.Ser94*]）、GALNS（c.319G>A [p.Ala107Thr]、c.860C>T [p.Ser287Leu]、c.1042A>G [p.Thr348Ala]）和IDUA（c.1A>C [p.Met1Leu]、c.1598C>G [p.Pro533Arg]、c.1562_1563insC [p.Gly522Argfs*50]）中常见变异的分布模式。我们庞大的患者队列揭示了伊朗MPS的遗传和地理情况，这为MPS的遗传流行病学提供了见解，并有助于基于区域特异性变异制定更具成本效益、更高效的诊断方法。
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