Lee Whiwon, Costain Gregory, Blaser Susan, Walker Susan, Marshall Christian R, Gonorazky Hernan, Inbar-Feigenberg Michal
Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Mol Genet Metab Rep. 2020 Oct 19;25:100664. doi: 10.1016/j.ymgmr.2020.100664. eCollection 2020 Dec.
Defects in are associated with a severe neonatal-lethal form of Zellweger spectrum disorder. We report two moderately affected siblings whose clinical and biochemical phenotypes expand the reported spectrum of -related disease. Genome sequencing of an adolescent male with progressive movement disorder, spasticity and neurodegeneration, and previous non-diagnostic plasma very-long chain fatty acid analysis, revealed a homozygous likely pathogenic missense variant in [c.991G > A; p.(Gly331Arg)]. A younger sibling with significant motor decline since the age of three years was also subsequently found to be homozygous for the familial variant. A comprehensive review of the scientific literature identified three additional families with non-lethal infantile- or childhood-onset -related disease, which together with this clinical report illustrate the potential for highly variable disease severity. Our findings demonstrate the diagnostic utility of genome-wide sequencing for identifying clinically and biochemically heterogeneous inherited metabolic disorders such as the peroxisome biogenesis disorders.
[基因名称]缺陷与一种严重的新生儿致死型泽尔韦格谱系障碍相关。我们报告了两名症状中等的患病同胞，他们的临床和生化表型扩展了已报道的与[基因名称]相关疾病的范围。对一名患有进行性运动障碍、痉挛和神经退行性变的青少年男性进行基因组测序，其之前的血浆极长链脂肪酸分析未得出诊断结果，结果发现该男性在[基因名称]中存在一个纯合的可能致病的错义变体[c.991G > A；p.(Gly331Arg)]。随后还发现一名自三岁起运动能力显著下降的年幼同胞也为该家族性[基因名称]变体的纯合子。对科学文献的全面回顾确定了另外三个患有非致死性婴儿期或儿童期发病的与[基因名称]相关疾病的家庭，连同本临床报告一起说明了疾病严重程度高度可变的可能性。我们的研究结果证明了全基因组测序在识别临床和生化异质性遗传性代谢疾病（如过氧化物酶体生物发生障碍）方面的诊断效用。
