具有复杂遗传结构的新型显性MPAN家族，作为表型变异的基础。
Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability.
作者信息
Balicza Peter, Bencsik Renata, Lengyel Andras, Gal Aniko, Grosz Zoltan, Csaban Dora, Rudas Gabor, Danics Krisztina, Kovacs Gabor G, Molnar Maria Judit
机构信息
Institute of Genomic Medicine and Rare Diseases (P.B., R.B., A.L., A.G., Z.G., D.C., M.J.M.), Semmelweis University, Budapest, Hungary; Neurology Outpatient Clinic (A.L.), General Medical Clinic, Motala Hospital, Sweden; Department of Neuroradiology (G.R.), and Department of Forensic and Insurance Medicine (K.D.), Semmelweis University, Budapest, Hungary; Tanz Centre for Research in Neurodegenerative Disease (G.G.K.), and Department of Laboratory Medicine and Pathobiology (G.G.K.), University of Toronto; and Laboratory Medicine Program (G.G.K.), University Health Network, Toronto, Canada.
出版信息
Neurol Genet. 2020 Sep 8;6(5):e515. doi: 10.1212/NXG.0000000000000515. eCollection 2020 Oct.
OBJECTIVE
Our aim was to study a Hungarian family with autosomal dominantly inherited neurodegeneration with brain iron accumulation (NBIA) with markedly different intrafamilial expressivity.
METHODS
Targeted sequencing and multiplex ligation-dependent probe amplification (MLPA) of known NBIA-associated genes were performed in many affected and unaffected members of the family. In addition, a trio whole-genome sequencing was performed to find a potential explanation of phenotypic variability. Neuropathologic analysis was performed in a single affected family member.
RESULTS
The clinical phenotype was characterized by 3 different syndromes-1 with rapidly progressive dystonia-parkinsonism with cognitive deterioration, 1 with mild parkinsonism associated with dementia, and 1 with predominantly psychiatric symptoms along with movement disorder. A heterozygous stop-gain variation in the gene segregated with the phenotype. Targeted sequencing of all known NBIA genes, and MLPA of and genes, as well as whole-genome sequencing in a trio from the family, revealed a unique constellation of oligogenic burden in 3 NBIA-associated genes ( p.Trp112Ter, p.Val105PhefsTer5, and dup(ex14)). Neuropathologic analysis of a single case (39-year-old man) showed a complex pattern of alpha-synucleinopathy and tauopathy, both involving subcortical and cortical areas and the hippocampus.
CONCLUSIONS
Our study expands the number of cases reported with autosomal dominant mitochondrial membrane protein-associated neurodegeneration and emphasizes the complexity of the genetic architecture, which might contribute to intrafamilial phenotypic variability.
目的
我们的目的是研究一个具有常染色体显性遗传的脑铁沉积神经退行性疾病（NBIA）的匈牙利家族，该家族成员间表现出明显不同的表型。
方法
对该家族中许多患病和未患病成员进行已知NBIA相关基因的靶向测序和多重连接依赖探针扩增（MLPA）。此外，进行了三联体全基因组测序以寻找表型变异的潜在解释。对一名患病家族成员进行了神经病理学分析。
结果
临床表型以3种不同综合征为特征——1种为快速进展性肌张力障碍-帕金森综合征伴认知功能减退，1种为轻度帕金森综合征伴痴呆，1种以精神症状为主并伴有运动障碍。 基因中的一个杂合性终止获得变异与该表型共分离。对所有已知NBIA基因进行靶向测序，对 基因和 基因进行MLPA，以及对该家族的一个三联体进行全基因组测序，结果显示在三个NBIA相关基因（p.Trp112Ter、p.Val105PhefsTer5和dup(ex14)）中存在独特的寡基因负荷组合。对一例（39岁男性）病例的神经病理学分析显示出α-突触核蛋白病和tau蛋白病的复杂模式，两者均累及皮质下和皮质区域以及海马体。
结论
我们的研究增加了常染色体显性线粒体膜蛋白相关神经退行性疾病的报告病例数，并强调了遗传结构的复杂性，这可能导致家族内表型变异。
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