A multidisciplinary approach for identifying and characterizing novel congenital malformation syndromes

识别和表征新型先天畸形综合征的多学科方法

• 批准号: 9769104
• 负责人: A.J. Agopian
• 金额: $ 40.82万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769104
• 关键词: Accounting; Address; Affect; Big Data; Biological Assay; Birth; Case Study; Catalogs; Child; Childhood; Clinic; Clinical; Congenital Abnormality; DNA; Data; Diagnosis; Disease Progression; Epidemiologist; Etiology; Evaluation; Family; Foundations; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic screening method; Goals; Health; Individual; Infant; International; Lead; Literature; Live Birth; Lysosomal Storage Diseases; Medical; Medical Genetics; Methods; Mutation; Nucleotides; Orphan; Orphan Drugs; Outcome; Parents; Pathway interactions; Patients; Pattern; Phenotype; Population; Prevention; Public Health; Rare Diseases; Recurrence; Registries; Reporting; Research; Review Literature; Sampling; Scheme; Structure; Syndrome; Variant; base; clinically significant; comparative genomic hybridization; cost; data registry; exome sequencing; expectation; experience; improved; interdisciplinary approach; malformation; novel; novel therapeutics; outcome forecast; population based; prevent; programs; rare condition; recruit; reproductive; success; targeted biomarker; therapeutic target; therapy development

Over 50% of children with multiple malformations seen in medical genetics clinics for a suspected genetic syndrome never receive a diagnosis, which leaves unanswered questions about prognosis and medical/reproductive planning. While individual multiple malformation syndromes (MMS) are rare diseases (many <1 in 200,000 births), in combination, these conditions are costly and medically severe. There have been some recent successes in developing orphan treatments for some of these rare syndromes, but this only represents the “tip of the iceberg,” and it is thought that there are many more recognized and unrecognized MMS that will be amenable to new therapies. The next steps toward identifying therapeutic targets and biomarkers of outcomes for these rare diseases are to 1) identify these MMS, 2) characterize their clinical profile, and 3) uncover the underlying genetic causes. To accomplish these goals, we will first identify “new” MMS (i.e., not described in the literature) using international data from two large networks that represent most of the major birth defects registries worldwide. By leveraging these population-based data, we will address the limitations of previous approaches for identifying new MMS (i.e., clinical case reports based on a small number of cases identified in a single clinic). Second, we will verify the occurrence of “unconfirmed” MMS (i.e., unconfirmed case reports of only a few cases) using our international network of birth defects registries to address the possibility that that the malformations patterns reported in these previous case reports occurred due to chance alone. We will use a network of medical genetics clinics we have assembled to recruit clinical patients with the new MMS and the unconfirmed MMS that we validate. We will conduct systematic phenotyping of these cases to better delineate the clinical profiles of these syndromes. We will also collect DNA samples from these patients and their families and conduct exome sequencing, which may identify pathways that could lead to therapeutic targets for these rare but clinically significant conditions.

在医学遗传学诊所，超过50%的儿童患有多种畸形