Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Institute for Informatics, Data Science and Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
J Neurodev Disord. 2024 Apr 17;16(1):17. doi: 10.1186/s11689-024-09530-3.
Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource's (ClinGen's) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen's BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.
单基因疾病在神经发育障碍的人群归因风险中占很大比例。然而，对于特定遗传变异与特定神经发育障碍之间因果关系的推断，往往缺乏必要的数据。为了应对这一科学障碍，13 个智力和发育障碍研究中心（IDDRC）成立了一个联盟，创建了大脑基因登记处（BGR），该登记处将临床遗传数据与假定大脑基因变异参与者的表型数据配对。表型谱是从电子健康记录（EHR）和一系列远程管理的标准化评估中汇编而成的，统称为快速神经行为评估协议（RNAP），其中包括认知、神经和神经精神病评估，以及注意力缺陷多动障碍（ADHD）和自闭症谱系障碍（ASD）的评估。BGR 参与者共同参与临床基因组资源（ClinGen）的 GenomeConnect 可在 ClinVar 中显示变异信息。BGR 目前包含 479 名参与者的数据，其中 55%为男性，6%为亚洲人，6%为黑人或非裔美国人，76%为白人，12%为西班牙裔或拉丁裔。BGR 中包含 200 多种基因，其中每个基因都有 12 个或更多参与者携带变异：CACNA1A、DNMT3A、SLC6A1、SETD5 和 MYT1L。超过 30%的变异是新生的，43%被归类为意义不明的变异（VUSs）。认知或发育筛查的平均标准分数低于 BGR 队列的平均值。EHR 数据显示，发育迟缓是该样本中最早和最常见的诊断，其次是言语和语言障碍、ASD 和 ADHD。BGR 数据已被用于加速 ClinGen 的 BGR 智力障碍（ID）-自闭症（ASD）基因验证专家小组评估的 36 个基因的基因-疾病有效性验证。总之，BGR 是对大脑基因感兴趣的利益相关者推进转化研究的资源，并继续招募具有临床报告变异的参与者，以建立一个丰富且特征良好的国家资源，促进神经发育障碍的研究。
