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

基本信息

批准号：
10443745
负责人：
A.J. Agopian
金额：
$ 38.04万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-25 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443745
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 Goals Health Individual Infant International Lead Literature Live Birth Lysosomal Storage Diseases Medical Medical Genetics Methods Nucleotides Orphan Orphan Drugs Outcome Parents Pathway interactions Patients Pattern Phenotype Population Prevention Prognosis Public Health Rare Diseases Recurrence Registries Reporting Research Review Literature Sampling Scheme Syndrome Variant base clinically significant comparative genomic hybridization cost data registry de novo mutation exome sequencing expectation experience genetic testing improved interdisciplinary approach malformation novel novel therapeutics population based prevent programs rare condition recruit reproductive success targeted biomarker therapeutic target therapy development

项目摘要

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.

超过 50% 的多发畸形儿童在医学遗传学诊所就诊疑似遗传综合症从未得到诊断，这留下了悬而未决的问题关于个体多发畸形的预后和医疗/生殖计划。综合征 (MMS) 是一种罕见疾病（许多人在 200,000 名新生儿中<1），综合起来，这些条件昂贵且医疗条件严峻，最近在这方面取得了一些成功。正在开发针对其中一些罕见综合征的孤儿疗法，但这仅代表 “冰山一角”，人们认为还有更多已被认可和未被认可的 MMS 将适合新疗法的下一步确定治疗方法。这些罕见疾病结果的目标和生物标志物是 1) 识别这些 MMS，2) 描述他们的临床特征，3) 揭示潜在的遗传原因。这些目标，我们将首先使用以下方法确定“新”MMS（即文献中未描述的）来自代表大多数主要出生缺陷的两个大型网络的国际数据通过利用这些基于人口的数据，我们将解决这些限制。以前用于识别新 MMS 的方法（即基于小型的临床病例报告）其次，我们将验证是否发生 “未经证实的”MMS（即仅少数病例的未经证实的病例报告）使用我们的国际出生缺陷登记网络，以解决畸形模式的可能性先前的案例报告中所报道的情况纯属偶然，我们将使用网络。我们组建了医学遗传学诊所，用新的 MMS 招募临床患者，我们将对这些病例进行系统表型分析。为了更好地描述这些综合征的临床特征，我们还将收集 DNA 样本。从这些患者及其家人身上进行外显子组测序，这可能会识别出可能导致这些罕见但具有临床意义的疾病的治疗靶点的途径。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Birth defects that co-occur with non-syndromic gastroschisis and omphalocele.

DOI：
10.1002/ajmg.a.61830
发表时间：
2020-11
期刊：
American journal of medical genetics. Part A
影响因子：
0
作者：
Oluwafemi OO;Benjamin RH;Navarro Sanchez ML;Scheuerle AE;Schaaf CP;Mitchell LE;Langlois PH;Canfield MA;Swartz MD;Scott DA;Northrup H;Ray JW;McLean SD;Ludorf KL;Chen H;Lupo PJ;Agopian AJ
通讯作者：
Agopian AJ

Prevalence and descriptive epidemiology of Turner syndrome in the United States, 2000-2017: A report from the National Birth Defects Prevention Network.

DOI：
10.1002/ajmg.a.63181
发表时间：
2023-05
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
影响因子：
2
作者：
Martin-Giacalone, Bailey A.;Lin, Angela E. E.;Rasmussen, Sonja A.;Kirby, Russell S.;Nestoridi, Eirini;Liberman, Rebecca F.;Agopian, A. J.;Carey, John C.;Cragan, Janet D.;Forestieri, Nina;Leedom, Vinita;Boyce, Aubree;Nembhard, Wendy N.;Piccardi, Monika;Sandidge, Theresa;Shan, Xiaoyi;Shumate, Charles J.;Stallings, Erin B.;Stevenson, Roger;Lupo, Philip J.
通讯作者：
Lupo, Philip J.

Patterns of co-occurring birth defects among infants with hypospadias.

DOI：
10.1016/j.jpurol.2020.11.015
发表时间：
2021-03
期刊：
Journal of pediatric urology
影响因子：
2
作者：
Ludorf KL;Benjamin RH;Navarro Sanchez ML;McLean SD;Northrup H;Mitchell LE;Langlois PH;Canfield MA;Scheuerle AE;Scott DA;Schaaf CP;Ray JW;Oluwafemi O;Chen H;Swartz MD;Lupo PJ;Agopian AJ
通讯作者：
Agopian AJ

Patterns of congenital anomalies among individuals with trisomy 13 in Texas.

DOI：
10.1002/ajmg.a.62175
发表时间：
2021-06
期刊：
American journal of medical genetics. Part A
影响因子：
0
作者：
Diaz D;Benjamin RH;Navarro Sanchez ML;Mitchell LE;Langlois PH;Canfield MA;Chen H;Scheuerle AE;Schaaf CP;Scott DA;Northrup H;Ray JW;McLean SD;Swartz MD;Ludorf KL;Lupo PJ;Agopian AJ
通讯作者：
Agopian AJ

Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability.

ADAT3 中的新错义变异是导致综合征性智力障碍的原因。

DOI：
10.1055/s-0039-1693151
发表时间：
2019
期刊：
Journal of pediatric genetics
影响因子：
0.4
作者：
Thomas,Elizabeth;Lewis,AndreaM;Yang,Yaping;Chanprasert,Sirisak;Potocki,Lorraine;Scott,DarylA
通讯作者：
Scott,DarylA