复发性纯合错义 DPM3 变异导致肌肉和大脑疾病,Clinical Genetics

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复发性纯合错义 DPM3 变异导致肌肉和大脑疾病
Clinical Genetics ( IF 2.9 ) Pub Date : 2022-08-06 , DOI: 10.1111/cge.14208
Sara Nagy _{1,

2} , Tracy Lau ₁ , Shahryar Alavi ₃ , Ehsan Ghayoor Karimiani ₄ , Jalal Vallian ₃ , Bobby G Ng ₅ , Samaneh Noroozi Asl ₆ , Javad Akhondian ₇ , Amir Bahreini ₈ , Omid Yaghini ₉ , Prech Uapinyoying ₁₀ , Carsten Bonnemann ₁₀ , Hudson H Freeze ₅ , Vajira H W Dissanayake ₁₁ , Nirmala D Sirisena ₁₁ , Miriam Schmidts ₁₂ , Henry Houlden ₁ , Andres Moreno-De-Luca ₁₃ , Reza Maroofian ₁

Affiliation

MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
Division of Genetics, Department of Cellular and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran.
Molecular and Clinical Sciences Institute, St. George's, University of London, London, UK.
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Pediatrics Endocrinology Department, Mashhad University of Medical Sciences, Mashhad, Iran.
Pediatric Neurology Department, Ghaem hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
Karyogen Medical Genetics Laboratory, Alzahra University, Isfahan, Iran.
Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Department of Anatomy, Genetics & Biomedical Informatics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.
Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Germany.
Autism & Developmental Medicine Institute, Genomic Medicine Institute, Department of Radiology, Diagnostic Medicine Institute, Danville, Pennsylvania, USA.

编码多萜醇磷酸甘露糖合酶亚基 ( DPM )的基因中的双等位基因致病变异是先天性糖基化障碍的罕见原因，DPM为糖基磷脂酰肌醇、 N-聚糖和蛋白质O-和C-甘露糖基化提供甘露糖基供体。DPM1和DPM2的致病性变异与肌肉-眼-脑 (MEB) 疾病相关，而DPM3变异主要发生在孤立性肌肉疾病——肌肉肌萎缩症患者中。到目前为止，只有一名患有复合杂合子DPM3的受影响个体已经描述了表现为肌病、轻度智力障碍、癫痫发作和侧脑室周围非特异性白质异常 (WMA) 的变体。在这里，我们展示了来自四个无关家庭的五个受影响的个体，他们患有从轻度到重度、小头畸形、癫痫、WMA、肌肉无力和可变心肌病的全球发育迟缓/智力残疾。先证者的外显子组测序揭示了一种超罕见的纯合致病性错义DPM3变异 NM_018973.4:c.221A>G, p.(Tyr74Cys)，它与所有家族的表型分离。单倍型分析表明该变体在三个家族中独立出现。功能分析未显示 N 有任何变化-变异引起的糖基化途径；然而，这并不排除其在 DPM 复合体和相关细胞通路功能中的致病性。该报告提供的支持证据表明，除DPM1和DPM2外， DPM3中的缺陷也可导致肌肉和大脑表型。

"点击查看英文标题和摘要"

A recurrent homozygous missense DPM3 variant leads to muscle and brain disease

Biallelic pathogenic variants in the genes encoding the dolichol-phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation, are rare causes of congenital disorders of glycosylation. Pathogenic variants in DPM1 and DPM2 are associated with muscle–eye–brain (MEB) disease, whereas DPM3 variants have mostly been reported in patients with isolated muscle disease—dystroglycanopathy. Thus far, only one affected individual with compound heterozygous DPM3 variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described. Here we present five affected individuals from four unrelated families with global developmental delay/intellectual disability ranging from mild to severe, microcephaly, seizures, WMA, muscle weakness and variable cardiomyopathy. Exome sequencing of the probands revealed an ultra-rare homozygous pathogenic missense DPM3 variant NM_018973.4:c.221A>G, p.(Tyr74Cys) which segregated with the phenotype in all families. Haplotype analysis indicated that the variant arose independently in three families. Functional analysis did not reveal any alteration in the N-glycosylation pathway caused by the variant; however, this does not exclude its pathogenicity in the function of the DPM complex and related cellular pathways. This report provides supporting evidence that, besides DPM1 and DPM2, defects in DPM3 can also lead to a muscle and brain phenotype.

更新日期：2022-08-06

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