背景:SINO综合征(痉挛性截瘫,智力残疾,眼球震颤和肥胖)是一种罕见的常染色体显性疾病,由KIDINS220中的杂合变体引起。报告共有12人,包括8个具有SINO和4个具有归因于双等位基因KIDINS220变体的常染色体隐性条件。
方法:在我们的国际队列中,我们有14个人,携带13种杂合子形式的新型致病性KIDINS220变体。我们评估了我们队列和先前报道的个体的临床和分子数据,并基于功能实验对KIDINS220相关疾病背后的发病机理有了更好的理解。
结果:使用胎儿组织和体外测定,我们证明了这些变体产生了KIDINS220截短的形式,这些形式错误地定位在点状的细胞内结构中,随着全长蛋白质水平的降低,表明了跨显性的负效应。92%的人在三年内得到了诊断,有发育迟缓的症状,痉挛,低张力,缺乏眼神交流和眼球震颤.我们确定了与胎儿脑积水相关的KIDINS220变体,并显示58%的受检个体表现出脑心室扩张。我们将SINO综合征的表型范围扩展到以前未强调的行为表现。
结论:我们的研究提供了对临床谱的进一步见解,KIDINS220变异的病因和预测的功能影响。
BACKGROUND: SINO syndrome (Spastic paraplegia, Intellectual disability, Nystagmus and Obesity) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising eight with SINO and four with an autosomal recessive condition attributed to bi-allelic KIDINS220 variants.
METHODS: In our international cohort, we have comprised 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed clinical and molecular data of our cohort and previously reported individuals and based on functional experiments reached a better understanding of the pathogenesis behind KIDINS220-related disease.
RESULTS: Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. 92% had their diagnosis within three years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted.
CONCLUSIONS: Our study provides further insights into the clinical spectrum, etiology and predicted functional impact of KIDINS220 variants.