Genomic Diagnosis in Children with Developmental Delay

描述（由申请人提供）：这个UMI提案的目标是解决技术、分析和伦理方面的挑战，这些挑战阻碍了DNA测序的最佳使用，以改善疾病的治疗和患者及其家属的生活规划。高通量DNA测序将用于满足发育迟缓、智力残疾和相关健康问题儿童（“DD/ID”）的主要诊断需求。DD/ID障碍给受影响的儿童及其家庭造成终身痛苦，是社会的一个主要保健和经济负担。它们通常很可能是由一个或几个在任何特定家庭中高度渗透的、通常是从头开始的突变驱动的，但大多数儿童无法准确诊断，这使得治疗和家庭咨询变得困难。事实上，许多受影响的家庭经历了“诊断奥德赛”，包括多年的检查和没有明确诊断的医生就诊。该提案建立了哈德逊阿尔法研究所的基因组学研究人员、伯明翰阿拉巴马大学附属的当地医学遗传学家以及路易斯维尔大学对伦理、法律和生物多样性感兴趣的研究人员之间的合作

DESCRIPTION (provided by applicant): The goal of this UMI proposal is to address the technological, analytical, and ethical challenges that prevent the optimal use of DNA sequencing to improve treatment of diseases and life planning for patients and their families. High-throughput DNA sequencing will be applied to meet the major diagnostic needs of children with developmental delay, intellectual disability, and related health problems ("DD/ID"). DD/ID disorders inflict life-long suffering for affected children and their families, and are a major heath care and economic burden to society. They are generally highly likely driven by one or a few highly penetrant, often de novo, mutations in any given family, but most children cannot be accurately diagnosed, making treatment and family counseling difficult. Indeed, many affected families undergo a "diagnostic odyssey", involving years of testing and doctor visits without a specific diagnosis. This proposal builds collaboration between genomics researchers at the Hudson Alpha Institute, local medical geneticists affiliated with the University of Alabama at Birmingham, and investigators at the University of Louisville interested in the ethical, legal, and social consequences of genetic information in the clinic. 600 children with DD/ID and their parents will be enrolled, consented, and questioned about their medical experiences and expectations about genetic information. 500 of these children and their parents will be subjected to a 2-stage sequencing plan: 1) "whole exome sequencing" and 2) "CNV sequencing". The former is a cost-effective strategy for identifying relevant variants, particularl for the early onset, severe, and often de novo phenotypes of DD/ID. The latter is a novel strategy with great potential to identify relevant regulatory mutations, which are ignored in typical clinical sequencing strategies. Medically relevant variants, either causal for DD/ID or incidental but predictive for other diseases, will be returned to the family by a medical geneticis and genetics counselor. Follow-up questionnaires and interviews will be used to determine the impact of the returned genomic information on clinical care, family planning, and other aspects of self-perception and well-being that may be altered as a result of the genetic diagnosis and incidental findings. Related questions about risks and benefits of probabilistic information and genomic information that does not lead to specific treatments will also be studied. This highly innovative study design will address a significant clinical need and important unmet challenges that slow or dilute the effectiveness of genomic information in the clinic.