A multidisciplinary approach for identifying and characterizing novel congenital malformation syndromes

超过50%的患有多种畸形的儿童在医学遗传学诊所接受治疗， 疑似遗传综合征从未得到诊断，这留下了未回答的问题 关于预后和医疗/生殖计划。个别多发畸形 综合征（MMS）是罕见的疾病（许多<1在200，000出生），在组合，这些 条件昂贵且医学上严重。最近在以下方面取得了一些成功： 为这些罕见综合征中的一些开发孤儿治疗，但这只代表了 “冰山一角”，人们认为还有许多更多的认可和未认可的 MMS将适用于新疗法。确定治疗方法的下一步 这些罕见疾病的目标和生物标志物的结果是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。完成 这些目标，我们将首先确定“新的”MMS（即，未在文献中描述）使用 来自两个大型网络的国际数据，代表了大多数主要出生缺陷 全球注册。通过利用这些基于人口的数据，我们将解决 用于识别新MMS的先前方法（即，临床病例报告基于一个小 在一个诊所发现的病例数）。第二，我们将核实 “未确认的”MMS（即，未经证实的病例报告，只有少数病例）使用我们的国际 出生缺陷登记网络，以解决畸形模式 在这些先前的病例报告中报告的发生仅是偶然。我们将使用网络 医学遗传学诊所，我们已经召集招募临床患者与新的MMS， 我们确认的未经确认的彩信我们将对这些病例进行系统的表型分析 以更好地描述这些综合征的临床特征。我们还会收集DNA样本 并进行外显子组测序， 这些途径可能导致这些罕见但具有临床意义的疾病的治疗靶点。

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.