背景:Schuurs-Hoeijmakers综合征,常染色体显性遗传神经发育障碍,是智力残疾(ID)的罕见原因,影响了全世界大约1%至3%的人。迄今为止,只有87起案件被记录在案,奇怪的是,它们中的大多数共享相同的突变(c.607C>T;p.R203W)。
方法:本研究报告了摩洛哥首例12岁女性PACS1综合征患者,在24名智力残疾患者的队列研究中发现。该综合征是由PACS1基因的从头突变引起的,位于11号染色体上,导致PACS1蛋白上的单个氨基酸修饰。异常蛋白质会破坏细胞运输过程,导致智力发育迟缓,面部畸形,和先天性异常。
结果:使用外显子组测序来鉴定基因突变,和Sanger测序验证了复发性突变的存在c.607C>T(p。Arg203Trp)在PACS1基因中。发现突变是杂合的,从头,这表明它不是从病人的父母那里遗传的。根据美国医学遗传学和基因组学学院(ACMG)标准进行的分类证实了其致病性,来自生物信息学分析的支持证据。该变体在人群数据库中的稀有性进一步支持了其致病性。
结论:这项研究扩展了我们对Schuurs-Hoeijmakers综合征的理解,一种全球报告病例有限的疾病。该疾病的遗传异质性凸显,复发突变是最常见的致病变异。功能研究表明PACS1在颅面发育和神经发育过程中的关键作用,与自闭症谱系障碍(ASD)的潜在影响。全面的遗传分析对于准确诊断和理解智力障碍的根本原因至关重要。需要进一步的研究来揭示与PACS1相关的神经发育障碍相关的机制和潜在的治疗靶点。
BACKGROUND: Schuurs-Hoeijmakers syndrome, an autosomal dominant neurodevelopmental genetic disorder, is a rare cause of intellectual disability (ID) affecting approximately 1 to 3% of all over the world. Only 87 cases have been recorded to date, and oddly enough, the majority of them share the same mutation (c.607 C > T; p.R203W).
METHODS: This study presents the first reported case in Morocco of a 12-year-old female patient with
PACS1 syndrome, identified during a cohort study of 24 patients with intellectual disability. The syndrome is caused by a de novo mutation of the
PACS1 gene, located on chromosome 11, resulting in a single amino acid modification on the
PACS1 protein. The abnormal protein disrupts cellular transport processes, leading to intellectual developmental delay, facial dysmorphia, and congenital anomalies.
RESULTS: Exome sequencing was employed to identify the genetic mutation, and Sanger sequencing validated the presence of the recurrent mutation c.607 C > T (p.Arg203Trp) in the
PACS1 gene. The mutation was found to be heterozygous and de novo, suggesting that it was not inherited from the patient\'s parents. Classification based on the American College of Medical Genetics and Genomics (ACMG) criteria confirmed its pathogenicity, with supporting evidence from bioinformatics analysis. The rarity of this variant in population databases further supports its pathogenic nature.
CONCLUSIONS: This study expands our understanding of Schuurs-Hoeijmakers syndrome, a disorder with limited reported cases globally. The genetic heterogeneity of the disorder is highlighted, with the recurrent mutation being the most common pathogenic variant. Functional studies indicate the crucial role of
PACS1 in craniofacial development and neurodevelopmental processes, with potential implications for autism spectrum disorders (ASD). Comprehensive genetic analyses are essential for accurate diagnosis and understanding the underlying causes of intellectual disabilities. Further research is warranted to unravel the mechanisms and potential therapeutic targets associated with PACS1-related neurodevelopmental disorders.