PDF(Pubmed)
Abstract：
Hereditary spastic paraplegias are a diverse group of degenerative disorders that are clinically categorized as isolated; with involvement of lower limb spasticity, or symptomatic, where spastic paraplegia is complicated by further neurological features. We sought to identify the underlying genetic causes of these disorders in the participating patients. Three consanguineous families with multiple affected members were identified by visiting special schools in the Punjab Province. DNA was extracted from blood samples of the participants. Exome sequencing was performed for selected patients from the three families, and the data were filtered to identify rare homozygous variants. ExomeDepth was used for the delineation of the copy number variants. All patients had varying degrees of intellectual disabilities, poor speech development, spasticity, a wide-based gait or an inability to walk and hypertonia. In family RDHR07, a homozygous deletion involving multiple exons and introns of SPG11 (NC000015.9:g.44894055_449028del) was found and correlated with the phenotype of the patients who had spasticity and other complex movement disorders, but not those who exhibited ataxic or indeterminate symptoms as well. In families ANMD03 and RDFA06, a nonsense variant, c.985C > T;(p.Arg329Ter) in DDHD2 and a frameshift insertion‒deletion variant of AP4B1, c.965-967delACTinsC;p.(Tyr322SerfsTer14), were identified which were homozygous in the patients while the obligate carriers in the respective pedigrees were heterozygous. All variants were ultra-rare with none, or very few carriers identified in the public databases. The three loss of function variants are likely to cause nonsense-mediated decay of the respective transcripts. Our research adds to the genetic variability associated with the SPG11 and AP4B1 variants and emphasizes the genetic heterogeneity of hereditary spastic paraplegia.
摘要：
遗传性痉挛性截瘫是一组不同的退行性疾病，在临床上被归类为孤立的;涉及下肢痉挛，或症状，痉挛型截瘫因进一步的神经系统特征而变得复杂。我们试图确定参与患者中这些疾病的潜在遗传原因。通过访问旁遮普省的特殊学校，确定了三个有多个受影响成员的近亲家庭。从参与者的血液样本中提取DNA。从三个家庭中选择的患者进行外显子组测序，并过滤数据以鉴定罕见的纯合变体。ExomeDepth用于描述拷贝数变体。所有患者均有不同程度的智力障碍,不良的语言发展，痉挛,广泛的步态或无法行走和高张力。在RDHR07家族中，发现了涉及SPG11的多个外显子和内含子的纯合缺失（NC000015.9：g.44894055_449028del），并与痉挛和其他复杂运动障碍患者的表型相关。但不是那些表现出共济失调或不确定症状的人。在ANMD03和RDFA06家族中，c.985C>T；（第Arg329Ter）在DDHD2中和AP4B1的移码插入-缺失变体，c.965-967delACTinsC；p。（Tyr322SerfsTer14），被鉴定为在患者中是纯合的，而在各自的谱系中的专性携带者是杂合的。所有变种都非常罕见，没有，或在公共数据库中确定的极少数运营商。功能变体的三种丧失可能导致各自转录物的无义介导的衰变。我们的研究增加了与SPG11和AP4B1变异相关的遗传变异性，并强调了遗传性痉挛性截瘫的遗传异质性。
