Oh Rachel Youjin, Maier Michael, Blaser Susan, Cameron Jessie, Hawkins Cynthia, Reversade Bruno, Yoon Grace
Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), Republic of Singapore.
J Med Genet. 2025 Feb 26;62(3):206-209. doi: 10.1136/jmg-2024-110419.
Biallelic pathogenic variants in cause a fatal autosomal recessive multisystem disorder characterized by recurrent autoinflammation, hypomyelination, progressive neurodegeneration, microcephaly, failure to thrive, liver dysfunction, respiratory chain defects and accumulation of glycogen in skeletal muscle. No missense variants in have been reported to date.We report a 6-year-old boy with microcephaly, global developmental delays, lower limb spasticity with hyperreflexia, epilepsy, abnormal brain MRI, failure to thrive, recurrent fevers and transaminitis. Whole-exome sequencing identified a homozygous missense c.320 C>G, p.(Pro107Arg) variant of uncertain significance (VUS) in Skeletal muscle biopsy showed active and chronic muscle fibre degeneration with deposits of periodic acid-Schiff-positive material in affected tissues, consistent with abnormal glycogen storage. Mitochondrial respiratory assays were normal in muscle tissue. Primary patient fibroblasts showed normal levels of mRNA expression but significantly reduced levels of endogenous C2ORF69 protein and GBE1 by Western blot. We report a patient with a homozygous missense variant in , causing loss of function. Depletion of endogenous GBE1 in affected cells can be considered a biomarker for this disorder and assist in the interpretation of VUS in This expands the clinical and genetic spectrum of -related disorder.
双等位基因致病性变异导致一种致命的常染色体隐性多系统疾病，其特征为反复发生的自身炎症、髓鞘形成减少、进行性神经退行性变、小头畸形、生长发育迟缓、肝功能障碍、呼吸链缺陷以及骨骼肌中糖原蓄积。迄今为止，尚未报道过该基因的错义变异。我们报告了一名6岁男孩，患有小头畸形、全面发育迟缓、下肢痉挛伴反射亢进、癫痫、脑部磁共振成像异常、生长发育迟缓、反复发热和转氨酶升高。全外显子组测序在该基因中鉴定出一个纯合错义c.320 C>G，p.(Pro107Arg)变异，意义不明（VUS）。骨骼肌活检显示受影响组织中有活跃和慢性肌纤维变性，伴有过碘酸希夫氏阳性物质沉积，与异常糖原储存一致。肌肉组织中线粒体呼吸测定正常。原代患者成纤维细胞显示mRNA表达水平正常，但通过蛋白质印迹法检测到内源性C2ORF69蛋白和GBE1水平显著降低。我们报告了一名患者，该基因存在纯合错义变异，导致功能丧失。受影响细胞中内源性GBE1的缺失可被视为该疾病的生物标志物，并有助于解释该基因中的意义不明变异。这扩展了与该基因相关疾病的临床和遗传谱。
