Our aim was to study a Hungarian family with autosomal dominantly inherited neurodegeneration with brain iron accumulation (NBIA) with markedly different intrafamilial expressivity.

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.

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 C19Orf12 gene segregated with the phenotype. Targeted sequencing of all known NBIA genes, and MLPA of PLA2G6 and PANK2 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 (C19Orf12 p.Trp112Ter, CP p.Val105PhefsTer5, and PLA2G6 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.

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.

我们的目的是研究一个匈牙利家庭，该家庭患有常染色体显性遗传性神经变性伴脑铁积累（NBIA），且家族内表达性显着不同。

对许多受影响和未受影响的家庭成员进行了已知 NBIA 相关基因的靶向测序和多重连接依赖性探针扩增 (MLPA)。此外，还进行了三重全基因组测序，以寻找表型变异的潜在解释。对一名受影响的家庭成员进行了神经病理学分析。

临床表型以 3 种不同的综合征为特征，其中 1 种为快速进行性肌张力障碍-帕金森症伴认知恶化，1 种为伴有痴呆的轻度帕金森症，1 种以精神症状为主并伴有运动障碍。 C19Orf12基因中的杂合停止增益变异与表型分离。对所有已知 NBIA 基因以及PLA2G6和PANK2基因的 MLPA 进行靶向测序，以及对来自该家族的三个基因组进行全基因组测序，揭示了 3 个 NBIA 相关基因（ C19Orf12 p.Trp112Ter、 CP）中独特的寡基因负荷群。 p.Val105PhefsTer5 和PLA2G6 dup(ex14))。对单个病例（39 岁男性）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，均涉及皮质下和皮质区域以及海马。

我们的研究扩大了常染色体显性线粒体膜蛋白相关神经变性的病例数量，并强调了遗传结构的复杂性，这可能导致家族内表型变异。