背景:兰姆-谢弗综合征(LAMSHF,OMIM:616803)是一种罕见的神经发育障碍,其特征是整体发育迟缓,智力残疾,糟糕的表达能力,其归因于染色体12p12上SOX5基因(SRY-盒转录因子5,HGNC:11201)的杂合变体的单倍体不足。全世界共报告113例,然而,仅报告了3例。在中国。这里,我们旨在报道SOX5基因的新变异体,并通过报道一系列中国LAMSHF患者的临床表型,为临床诊断提供范例.
方法:本研究回顾性收集中国LAMSHF患者家属的资料。进行全外显子组测序(WES)以确认4例无法解释的发育迟缓或癫痫患儿的诊断。使用小基因剪接测定来验证剪接变体是否影响剪接。同时,对LAMSHF患者的临床和遗传学特征进行了文献复习分析.
结果:3例LAMSHF患者分别在SOX5基因中出现了从头杂合突变,c.290delC(p.Pro97fs*30),chr12:23686019_24048958del,c.1772-1C>A,剩下的一个有他父亲遗传的突变,c.1411C>T(p。Arg471*).这些儿童的主要临床表现表现为全球发育迟缓,其中一人也有癫痫发作。小基因实验结果表明,剪接变体,c.1772-1C>A,转录了一种新的mRNA产物,该产物导致截短的蛋白质的形成。
结论:通过对现有文献的全面回顾和分析,本研究显示智力残疾,言语延迟和面部畸形是常见的临床表现,而癫痫发作和脑电图异常罕见(21/95,22.16%)。值得注意的是,我们代表了亚洲最大的LAMSHF样本量,包括以前未报道的SOX5基因突变,并且已经进行了小基因测试以验证c.1772-1C>A剪接变体的致病性。该研究进一步扩展了LAMSHF的表型和基因型,同时为基因位点的潜在致病性提供了新的见解。
BACKGROUND: Lamb-Shaffer syndrome (LAMSHF, OMIM: 616803) is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, which is attributed to haploinsufficiency by heterozygous variants of SOX5 gene (SRY-Box Transcription Factor 5, HGNC: 11201) on chromosome 12p12. A total of 113 cases have been reported in the world, however, only 3 cases have been reported.in China. Here, we aimed to report novel variants of SOX5 gene and provide examples for clinical diagnosis by reporting the clinical phenotype of a series of Chinese patients with LAMSHF.
METHODS: This study retrospectively collected the information of families of LAMSHF patients in China. Whole Exome Sequencing (WES) were performed to confirm the diagnosis of 4 children with unexplained developmental delay or epilepsy. A minigene splicing assay was used to verify whether the splice variant affected splicing. Meanwhile, a literature review was conducted to analyze the clinical and genetic characteristics of patients with LAMSHF.
RESULTS: Three of the LAMSHF patients had a de novo heterozygous mutation in the SOX5 gene respectively, c.290delC (p.Pro97fs*30), chr12:23686019_24048958del, c.1772-1C > A, and the remaining one had a mutation inherited from his father, c.1411C > T (p.Arg471*). The main clinical manifestations of these children were presented with global developmental delays, and one of them also had seizures. And the results of the minigene experiment indicated that the splice variant, c.1772-1C > A, transcribed a novel mRNA product which leaded to the formation of a truncated protein.
CONCLUSIONS: Through a comprehensive review and analysis of existing literature and this study showed intellectual disability, speech delay and facial dysmorphisms were common clinical manifestation, while the seizures and EEG abnormalities were rare (21/95, 22.16%). Notably, we represent the largest sample size of LAMSHF in Asia that encompasses previously unreported SOX5 gene mutation, and a minigene testing have been conducted to validate the pathogenicity of the c.1772-1C > A splice variant. The research further expands the phenotype and genotype of LAMSHF while offers novel insights for potential pathogenicity of genes locus.