RESEARCH COMPONENT

研究部分

基本信息

批准号：
8846268
负责人：
MARY A WILSON
金额：
$ 30.25万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8846268
关键词：
Affect Behavior Bite Bruck-de Lange syndrome Candidate Disease Gene Cessation of life Child Child health care Chronic Clinical Disease Epidemiologic Studies Etiology Eye Family Fathers Genetic Genetic Heterogeneity Hair Head Banging Heterogeneity Individual Injury Intellectual functioning disability Knock-out Lead Lesch-Nyhan Syndrome Measures Mental Retardation and Developmental Disabilities Research Centers Mothers Nucleotides Outcome Pathway interactions Patients Persons Pharmacological Treatment Prevalence Production Quality of life Risk Self-Injurious Behavior Series Severities Single Nucleotide Polymorphism Syndrome Therapeutic Tissues Treatment Protocols Variant autism spectrum disorder base clinical phenotype disability evidence base exome sequencing genetic pedigree intellectual and developmental disability medical complication next generation sequencing social

项目摘要

Self-injurious behavior (SIB) is among the most serious conditions affecting individuals with intellectual disability (ID). It is characterized by production of physical injury to the individual's own body, resulting in tissue damage [1]. The most common topographies of SIB include head banging, self-biting, eye poking, selfscratching, hair pulling, and self-hitting. While definitive epidemiological studies have not yet been performed [2], the prevalence of SIB is estimated at 5 to 32% of persons with ID or autism spectrum disorder (ASD) [3-7]. Chronic SIB is associated with medical complications, restricted educational, vocational, and social opportunities, residential or institutional placement and poor long-term outcome [8]. In severe cases, SIB may produce permanent tissue damage or in extreme cases, death. Thus, SIB often has devastating adverse impacts on child health, family functioning, and quality of life. With the recent emergence of both single nucleotide polymorphism (SNP) arrays and next-generation sequencing, it has become possible to determine the genetic basis of a series of clinical disorders. Recent studies suggest a substantial contribution to ID risk from de novo copy number variants (CNVs) such as those measured using SNP arrays; from de novo single nucleotide variants (SNVs) such as those identified from whole exome sequencing of father/mother/child trios; and from rare complete (homozygous) knockouts. We propose to determine genetic contributions to SIB when it occurs in individuals with unknown etiology, hypothesizing that we will see significant genetic contribution to their clinical phenotypes, given the extreme severity of their disability and clinical profile. Because the vast majority of these cases are simplex (i.e. there is only one affected individual per pedigree), we hypothesize that dominant, de novo variants (CNVs and/or SNVs) will be found to be associated with SIB. Several genetic syndromes that are associated with self-injury, such as Lesch-Nyhan Syndrome and Cornelia de Lange Syndrome, implicate underlying genetic mechanisms as a possible cause of SIB. The patients we propose to study have very dramatic clinical phenotypes, and while their behaviors are studied intensively as part of a treatment regimen, there have been few studies to characterize the genetic bases of the disorders. There is expected to be some genetic heterogeneity underlying self-injury, and yet the clinical heterogeneity is consistent with the hypothesis that the disruption of common pathways may be important. We propose to identify candidate genes associated with SIB that may potentially lead to evidence-based pharmacological treatment or other therapeutic approaches.

自残行为 (SIB) 是影响智力低下者的最严重的状况之一残疾（ID）。它的特点是对个体自身产生物理伤害，导致组织损伤损害[1]。 SIB 最常见的形态包括撞头、自咬、戳眼、自抓、拉头发、自打。虽然尚未进行明确的流行病学研究 [2]，据估计，ID 或自闭症谱系障碍 (ASD) 患者的 SIB 患病率为 5% 至 32% [3-7]。慢性 SIB 与医疗并发症、教育、职业和社会限制有关机会、居住或机构安置以及不良的长期结果[8]。情况严重时，SIB可能会造成永久性组织损伤，或者在极端情况下导致死亡。因此，SIB 经常会产生毁灭性的不利影响。对儿童健康、家庭功能和生活质量的影响。随着最近单核苷酸多态性 (SNP) 阵列和下一代芯片的出现通过测序，确定一系列临床疾病的遗传基础成为可能。最近的研究表明，从头拷贝数变异 (CNV) 对 ID 风险有重大贡献，例如使用 SNP 阵列测量；来自 de novo 单核苷酸变体 (SNV)，例如从父/母/子三人组的全外显子组测序；以及罕见的完全（纯合）敲除。我们当 SIB 发生在病因不明的个体中时，建议确定 SIB 的遗传因素，假设我们将看到其临床表型的显着遗传贡献，考虑到极端情况他们的残疾严重程度和临床特征。因为绝大多数这些情况都是单一的（即有每个谱系只有一个受影响的个体），我们假设显性的从头变异（CNV 和/或 SNV）将被发现与 SIB 相关。几种与自残有关的遗传综合症，例如 Lesch-Nyhan 综合症和 Cornelia de Lange 综合征，暗示潜在的遗传机制是 SIB 的可能原因。这我们建议研究的患者具有非常显着的临床表型，并且在研究他们的行为时作为治疗方案的一部分，很少有研究来描述其遗传基础的疾病。预计自伤背后存在一些遗传异质性，但临床上异质性与共同途径的破坏可能很重要的假设是一致的。我们提议识别与 SIB 相关的候选基因，这些基因可能会导致基于证据的药物治疗或其他治疗方法。