背景:CorneliadeLange(CdLS)是一种罕见的遗传性疾病,会影响大多数身体系统。包括NIPBL和SMC1A在内的多个基因的变异,会导致综合症。迄今为止,关于CdLS个体基因型-表型关联的文献非常有限,尽管研究表明,不同变异的临床表型严重程度存在一些差异。这项研究旨在检查和比较CdLS基因的神经行为差异和发育变异性,特别是NIPBL和SMC1A,并确定基因型-表型相关性。
方法:这项患者报告的结果研究包括从Sanford的“罕见疾病协调”注册中心获取数据。共有26名患有CdLS和已知NIPBL变异的儿童/成人的父母(平均年龄=20.46岁,SD=11.21)和12具有SMC1A中的已知变体(平均年龄=11.08岁,SD=9.04)完成了一系列有关其孩子发育历史的问卷调查。这包括达到共同语言和运动里程碑,干预史,和行为功能。在变体组中比较了发育历史和报告的行为调节困难。
结果:总体而言,在NIPBL或SMC1A中具有致病变异体的个体在运动和语言里程碑中也有类似的延迟,约70%的人在5岁时不使用短语语言,30-50%的人在5岁时不行走.然而,那些具有NIPBL变体的人在行为表型上表现出更严重的程度,也就是说,重复的行为,发脾气,和退缩的行为。此外,这些个体比具有SMC1A变体的个体更有可能表现出自我伤害行为,和焦虑。两组参与者参与言语和职业治疗的比例相似,然而,SMC1A变异体的患者更有可能进行物理治疗.尽管很大一部分参与者从未掌握单个单词或句子的使用,但两个临床组报告的交流或辅助设备使用率较低。
结论:研究结果与最近强调更严重行为表型的调查一致,特别是自闭症特征,焦虑,和行为监管挑战,在具有NIPBL变体的那些中,尽管具有可比的发展里程碑。两组都认可非常高的注意力问题。研究结果强调了早期干预的重要性,包括行为健康服务。
BACKGROUND: Cornelia de Lange (CdLS) is a rare genetic disorder that affects most body systems. Variants in multiple genes including NIPBL and SMC1A, can cause the syndrome. To date, literature on genotype-phenotype associations in individuals with CdLS is extremely limited, although studies suggest some differences in clinical phenotype severity across variants. This study aimed to examine and compare neurobehavioral differences and developmental variability across CdLS genes, specifically NIPBL and SMC1A, and identify genotype-phenotype correlations.
METHODS: This patient-reported outcomes study included accessing data from the Coordination of Rare Diseases registry at Sanford. Parents of a total of 26 children/adults with CdLS and a known variant in NIPBL (Mean age = 20.46 years, SD = 11.21) and 12 with a known variant in SMC1A (Mean age = 11.08 years, SD = 9.04) completed a series of questionnaires regarding their child\'s developmental history. This included attainment of common language and motor milestones, intervention history, and behavior functioning. Developmental history and reported behavior regulation difficulties were compared across variant groups.
RESULTS: Overall, individuals with a pathogenic variant in NIPBL or SMC1A were similarly delayed across motor and language milestones with about 70% not using phrase speech and 30-50% not walking by 5 years of age. However, those with NIPBL variants showed more severity in behavioral phenotype, namely with more repetitive behaviors, tantrums, and withdrawn behaviors. In addition, these individuals were more likely than those with SMC1A variants to demonstrate self-injurious behaviors, and anxiety. Both groups yielded a similar proportion of participants who participated in speech and occupational therapy, however those with SMC1A variants were more likely to engage in physical therapy. Both clinical groups report low rate of communicative or assistive device use despite a large proportion of participants never mastering single word or sentence use.
CONCLUSIONS: Study results are consistent with recent investigations highlighting more severe behavioral phenotype, particularly autistic features, anxiety, and behavior regulation challenges, among those with NIPBL variants albeit comparable developmental milestones. Both groups endorsed very elevated attention problems. Findings highlight importance of early interventions, including behavioral health services.