A multidisciplinary approach for identifying and characterizing novel congenital malformation syndromes

超过50%的患有多发性畸形的儿童在医学遗传学诊所就诊 疑似遗传综合症永远不会得到诊断，这留下了一些悬而未决的问题 关于预后和医疗/生殖计划。而个体多发性畸形 综合征(MMS)是一种罕见的疾病(每200,000名新生儿中就有1名)，这些疾病结合在一起 条件是昂贵的，医疗上也很严峻。最近在以下方面取得了一些成功 为一些罕见的综合症开发孤儿治疗方法，但这只代表了 “冰山一角”，人们认为还有更多的人被认可和未被认可 可以接受新疗法的彩信。确定治疗方法的下一步 这些罕见疾病的治疗目标和预后生物标记物是：1)确定这些MMS，2) 描述他们的临床特征，以及3)揭示潜在的遗传原因。要完成 为了实现这些目标，我们将首先使用以下方法确定“新的”彩信(即文献中没有描述的彩信 来自两个代表大多数主要出生缺陷的大型网络的国际数据 世界各地的注册处。通过利用这些基于人口的数据，我们将解决这些限制 以前识别新的MMS的方法(即，基于小规模的 在一家诊所发现的病例数)。第二，我们将核实发生了 “未经证实”彩信(即只有几例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 在这些以前的病例中，报告的发生完全是偶然的。我们将使用一个网络 我们已经召集了医学遗传学诊所来招募有新的MMS和 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鉴定。 以更好地描述这些综合征的临床特征。我们还将收集DNA样本 并进行外显子组测序，这可能会识别 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。

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.