痉挛型截瘫和精神运动发育迟缓伴或不伴癫痫发作(SPPRS,OMIM616756)是由HACE1基因的双等位基因致病变异所惹起的罕见遗传病。最初,据报道,这些突变与肿瘤易感性有关.尽管如此,通过2015年的全外显子组测序,HACE1突变被认为是一种新的常染色体隐性遗传神经发育障碍的原因,其特征是痉挛,肌张力减退,智力残疾。迄今为止,已经描述了14个HACE1致病性变体;这些变体具有功能丧失效应,导致具有不同严重度的临床表现。然而,尚未提及HACE1基因中的严重缺失是导致痉挛性截瘫的原因。这里,我们报告了一例2岁男性痉挛的临床病例,主要影响下肢,和发育迟缓。外显子组测序,染色体微阵列分析,和mRNA分析用于鉴定致病基因。我们发现临床发现是由于先前未描述的HACE1双等位基因缺失。我们确定了外显子7:c的缺失。(5341_535-1)_(6171_618-1)del(NM_020771.4)和6q16.3基因座中的总缺失,影响整个HACE1基因:g.105018931_105337494del,(GRCh37)。由于可能存在错误的纯合性结果,因此需要对HACE1中具有原始纯合性突变的患者进行全面的诊断方法。据报道超过80%的所述突变是纯合的。初始半合子很难通过定量方法检测,这可能会对痉挛性截瘫患者的分子诊断鉴定提出挑战。
Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS, OMIM 616756) is a rare genetic disease caused by biallelic pathogenic variants in the
HACE1 gene. Originally, these mutations have been reported to be implicated in tumor predisposition. Nonetheless, via whole exome sequencing in 2015,
HACE1 mutations were suggested to be the cause of a new autosomal recessive neurodevelopmental disorder, which is characterized by spasticity, muscular hypotonia, and intellectual disability. To date, 14
HACE1 pathogenic variants have been described; these variants have a loss-of-function effect that leads to clinical presentations with variable severities. However, gross deletions in the
HACE1 gene have not yet been mentioned as a cause of spastic paraplegia. Here, we report a clinical case involving a 2-year-old male presenting with spasticity, mainly affecting the lower limbs, and developmental delay. Exome sequencing, chromosomal microarray analysis, and mRNA analysis were used to identify the causative gene. We revealed that the clinical findings were due to previously undescribed
HACE1 biallelic deletions. We identified the deletion of exon 7: c.(534+1_535-1)_(617+1_618-1)del (NM_020771.4) and the gross deletion in the 6q16.3 locus, which affected the entire HACE1 gene: g.105018931_105337494del, (GRCh37). A comprehensive diagnostic approach for the patients with originally homozygous mutations in HACE1 is required since false homozygosity results are possible. More than 80% of the described mutations were reported to be homozygous. Initial hemizygosity is hard to detect by quantitative methods, and this may challenge molecular diagnostic identification in patients with spastic paraplegia.