背景:遗传性痉挛性截瘫-81是最近发现的一种,罕见的常染色体隐性疾病,由于SELENOI基因的双等位基因致病变异,到目前为止,只有两个家庭被报告。在先前两个受影响的家庭中记录的特征包括感音神经性耳聋,失明,腭裂,电机发育延迟,运动技能的回归,智力发育受损,不良的言语和语言习得,痉挛,反射亢进,白质异常,大脑和小脑萎缩.
方法:在本研究中,我们对一个有两个患侧同胞的单一家庭进行了外显子组测序分析,以确定复杂性遗传性痉挛性截瘫的遗传原因.Sanger测序进一步证实了这一结果,cDNA分析和3D蛋白质建模。
结果:外显子组测序鉴定了一个纯合的,SELENOI基因中的同义变体(NM_033505.4:c.126G>A:p。(Lys42Lys)在两个兄弟姐妹中。Sanger测序证实了父母双方的杂合状态与常染色体隐性遗传一致。已发现该变体破坏正常剪接,并可能导致外显子2的跳过,导致SELENOIN端23个氨基酸的框内缺失[NM_033505.4:c.57_126del:p。(Tyr20_Lys42del)]进一步导致蛋白质的结构变化。
结论:我们报告了SELENOI基因中一种新的纯合同义变异,导致两名遗传性痉挛性截瘫81患者的剪接异常。该报告进一步扩展了遗传性痉挛性截瘫81的表型和基因型谱。
Hereditary spastic paraplegia 81 is a recently identified, rare autosomal recessive disease, caused by biallelic pathogenic variants in the
SELENOI gene, with only two families reported to date. The features documented in the two previous affected families include sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities and cerebral and cerebellar atrophy.
In the present study, we performed exome sequencing analysis in a single family with two affected siblings to identify the genetic cause of complicated hereditary spastic paraplegia. The results were further confirmed by Sanger sequencing, cDNA analysis and 3D protein modelling.
Exome sequencing identified a homozygous, synonymous variant in the
SELENOI gene (NM_033505.4:c.126G>A:p.(Lys42Lys)) in both of the siblings. Sanger sequencing confirmed the heterozygous status in both parents consistent with the autosomal recessive inheritance. This variant has been found to disrupt normal splicing and lead to skipping of exon 2, causing in-frame deletion of
SELENOI N-terminal 23 amino acids [NM_033505.4:c.57_126del:p.(Tyr20_Lys42del)] and further leading to structural changes in the protein.
We report a novel homozygous synonymous variant in the
SELENOI gene causing abnormal splicing in two patients affected with hereditary spastic paraplegia 81. This report further expands the phenotypic and genotypic spectrum of hereditary spastic paraplegia 81.