PROJECT I; POLYGENIC CAUSES of ISOLATED and NON-SYNDROMIC CONGENITAL

为了实现该计划项目的具体目标，我们在项目I(孤立或非综合征型先天性隔疝(CDH)的多基因病因将由罕见的单基因CDH告知)中组建了一支才华横溢的团队，由首席研究员Barbara Pober医学博士和Jay Wilson医学博士领导。 威尔逊博士构思和培育了一家最令人印象深刻的先天性横隔疝患者随访诊所，为全国其他诊所树立了榜样。它的跨学科性质提供了广泛的护理，以满足CDH幸存者的需求，这些患者通常患有严重的支气管肺发育不良，伴随着胃食道反流引起的进食障碍，并导致持续的肺损伤，由于进食困难而无法茁壮成长，以及相关的听力异常和神经疾病，尤其是在那些患有综合征性CDH的患者中。此外，威尔逊博士还直接负责这些患者在体外膜氧合(ECMO)期间以及在修复横隔膜和其他相关先天性畸形的多个外科手术过程中的管理。他与波士顿儿童医院的儿科外科医生团队合作，多纳霍医生与马萨诸塞州儿童综合医院的团队合作。事实上，这两个地点的所有患者都参加了这项研究，这要归功于他们的父母的慷慨，以及他们在寻找这些异常的遗传原因方面的投入。这导致了这两个机构在这一扩大赠款过程中的应计比率约为90%。 医学博士Barbara Pober是世界领先的遗传学家之一，研究CDH。她 她亲自对所有患者进行表型鉴定，并将他们输入到她与丹尼·肖在波士顿儿童医院设计的数据库中，然后将临床数据输入其中。在手术室里，她仔细的表型鉴定与每位外科医生非常精确的横隔膜缺陷的位置和严重程度的记录相匹配，以确定表型。Pober博士与她在世界各地的同事一起工作；她受到同事们的专业尊重，这导致了我们成功地建立了信息丰富的多元化家庭。她直接监督儿童医院和马萨诸塞州儿童综合医院的研究协调员进行适当的确定，收集标本，并将其适当地分配给马萨诸塞州综合医院，以提取DNA，并创建淋巴母细胞或成纤维细胞系。Pober博士与多纳霍博士、研究员和项目协调员合作，将标本流向适当的实验室，并收集、解释和整合结果数据。 为每个有多个CDH患者的家庭绘制家系，并尝试记录是否存在血缘关系。在目前的赠款间隔期间，已经制定了检查近亲家庭单身人士的策略，以便检查通过体面或杂合性丢失(LOH)显示身份的区域是否存在伴随的拷贝数变异(CNV)。据认为，这种在LOH地区的CNV的重合发生在大约10%的血缘独生子女中，这使得这种方法值得采用。 Caroline Coletti，M.S.，我们的项目协调员，通过管理核心保持标本的流动，并在多个站点之间报告结果，共同实现该项目的目标。 她和多纳霍博士将与每个项目I、II和III的首席调查员以及核心董事合作，选择适当的研究平台，并收集数据以供后续存储和解释。他们将每两周在现场或通过视频会议开会，并规划外部咨询委员会的投入和评价。他们还将计划手稿、进度报告，并批准续签。

To address the Specific Aims of the Program Project we have assembled a talented team in PROJECT I (Polygenic Causes of Isolated or Non-Syndromic Congenital Diaphragmatic Hernia (CDH) will be Informed by Rare Monogenic CDH) headed by Principal Investigators Barbara Pober, MD, and Jay Wilson,MD. Dr. Wilson has conceived and nurtured one of the most impressive follow up clinics for patients with congenital diaphragmatic hernia which has served as a model for other clinics around the country. Its interdisciplinary nature provides a broad spectrum of care to address the needs of CDH survivors who often have severe bronchopulmonary dysplasia accompanied by feeding disorders caused by gastroesophageal reflux and contributing to continued lung injury, failure to thrive because of feeding difficulties, and associated hearing abnormalities and neurological disorders particularly in those patients with syndromic CDH. Dr. Wilson, in addition, has direct responsibilities for managing these patients while on extracorporeal membrane oxygenation (ECMO) and during their multiple surgical procedures directed toward repair of the diaphragm and other associated congenital anomalies. He works with a team of pediatric surgeons at the Children's Hospital Boston and Dr. Donahoe works with the team at the Mass General Hospital for Children. Virtually all of the patients at both sites have been enrolled into the study due to the generosity of their parents and their investment In finding the genetic causes of these anomalies. This has resulted In an approximately ninety percent accrual rate at both institutions over the course of this expanding grant. Dr. Barbara Pober, M.D., is one of the leading geneticists in the world in the study of CDH. She personally phenotypes all of the patients and enters them into a database which she designed with Danny Shaw at the Children's Hospital Boston, into which clinical data is entered. Her careful phenotyping is matched in the operating room by the very precise documentation of the location and the severity of the diaphragm defect by each surgeon to define the phenotype. Dr. Pober has worked with her colleagues all over the world; the professional regard with which she is held by her colleagues has lead to our successful accrual of informative multiplex families. She directly supervises the study coordinators based both at Children's and at Mass General Hospital for Children for appropriate ascertainment, collection of specimens and their proper disbursement to the Massachusetts General Hospital for the extraction of DNA, and the creation of lymphoblast or fibroblast cell lines. Dr. Pober works with Dr. Donahoe, the research fellows, and the Program Coordinator to direct the flow of specimens to appropriate laboratories and to collect, interpret, and integrate resulting data. Family pedigrees are drawn for each family with multiple affected patients with CDH and attempts are made to document if consanguinity is present. During the course of the present grant interval, strategies to examine singletons from consanguineous families have been devised so that regions showing identity by decent or loss of heterozygosity (LOH) are examined for concomitant copy number variants (CNVs). It Is thought that this coincidence of CNVs in regions of LOH occurs in about ten percent of the consanguineous singletons which makes this approach worthwhile to undertake. Caroline Coletti, M.S., our program coordinator, maintains the flow of specimens via the administration core and reports results between the multiple sites working together to achieve the goals of this Program Project. She and Dr. Donahoe will work with the Principal Investigators of each Project I, II, and III, and the Core Directors to select the appropriate platform for study and to collect data for subsequent storage and interpretation. They will meet every two weeks on site or by video conferencing and plan External Advisory Committee input and evaluation. They will also plan manuscripts, progress reports, and grant renewals.