Molecular Genetic Analysis of Congenital Diaphragmatic Hernia

先天性膈疝的分子遗传学分析

• 批准号: 8068823
• 负责人: ANNE M. SLAVOTINEK
• 金额: $ 12.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068823
• 关键词: Abdomen; Affect; Candidate Disease Gene; Chest; Chromosome Deletion; Chromosomes; Congenital Abnormality; Congenital diaphragmatic hernia; Counseling; Cytogenetics; Data; Development; Diaphragmatic Hernia; Etiology; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Goals; Hernia; Human; Individual; Infant Mortality; Knowledge; Life; Maps; Molecular Genetics; Morbidity - disease rate; Mus; Muscle; Mutation; Pathogenesis; Patients; Public Health; Publishing; Research; Respiratory Diaphragm; Techniques; Tendon structure; Tissues; Transcript; base; cohort; comparative genomic hybridization; family management; gene function; genetic analysis; improved; loss of function; malformation; mortality; stillbirth

DESCRIPTION (provided by applicant): Our overall goal is to identify the genetic causes of diaphragmatic hernia in humans. The diaphragm is a tissue composed of muscle and tendon that separates the chest and abdomen. If the diaphragm does not form normally, a hernia or protrusion of the abdominal contents into the chest can result. Diaphragmatic hernias are common and occur in 1 in 2500 live- and stillbirths. A diaphragmatic hernia is a devastating birth defect, and the mortality and morbidity associated with the hernias is very high. Little is known about the genetic causes of diaphragmatic hernia, and we therefore would like to discover which genes are important in determining which babies is susceptible to developing a hernia. We have used a technique called array comparative genomic hybridization to identify new, small chromosome deletions in patients with diaphragmatic hernias. These deleted regions contain genes that are needed for normal diaphragm development. We would like to develop this research further and use the same technique to continue to screen patients with diaphragmatic hernias for chromosome deletions. We would also like to determine which of the genes in the deleted regions are involved in diaphragm development. To do this, we propose to determine which of the genes from the deleted regions are expressed in the mouse diaphragm, as we hypothesize that the genes expressed in the mouse diaphragm will also be expressed in the human diaphragm. We will then compile a list of candidate genes for diaphragmatic hernias based on gene expression and published data on gene expression and function. We will sequence the candidate genes in a large cohort of patients with diaphragmatic hernias. Our purpose is to detect the genes that cause the hernias to improve patient counseling and to advance our understanding of the pathogenesis of this birth defect. Relevance to Public Health This project is directed at improving our understanding of the genetic causes of a common birth defect, congenital diaphragmatic hernia. An increase in our knowledge about the genes that cause some individuals to be affected and not others will allow us to optimize treatment and management for the families concerned and thus may help to reduce infant mortality and morbidity.

描述（由申请人提供）：我们的总体目标是确定人类膈疝的遗传原因。横膈膜是由肌肉和肌腱组成的组织，将胸部和腹部分开。如果横膈膜不能正常形成，就会导致疝气或腹部内容物突出到胸部。膈疝很常见，活产和死产的发生率为1 / 2500。膈疝是一种毁灭性的出生缺陷，与疝相关的死亡率和发病率很高。关于膈疝的遗传原因所知甚少，因此我们希望发现哪些基因在决定哪些婴儿易患疝气方面起重要作用。我们使用了一种称为阵列比较基因组杂交的技术来识别膈疝患者中新的小染色体缺失。这些缺失的区域包含正常横膈膜发育所需的基因。我们希望进一步发展这项研究，并使用相同的技术继续筛查膈疝患者的染色体缺失。我们还想确定哪些缺失区域的基因与横膈膜发育有关。为了做到这一点，我们建议确定来自删除区域的哪些基因在小鼠横膈膜中表达，因为我们假设在小鼠横膈膜中表达的基因也会在人类横膈膜中表达。然后，我们将根据基因表达和已发表的基因表达和功能数据编制膈疝候选基因列表。我们将对大量膈疝患者的候选基因进行测序。我们的目的是检测导致疝气的基因，以改善患者咨询，并提高我们对这种出生缺陷发病机制的理解。该项目旨在提高我们对一种常见出生缺陷——先天性膈疝的遗传原因的理解。我们对导致某些个体而不是其他人受到影响的基因的了解的增加，将使我们能够为有关家庭优化治疗和管理，从而可能有助于降低婴儿死亡率和发病率。

项目成果

A de novo deletion of CALN1 in a male with a bilateral diaphragmatic defect does not definitely cause this malformation.

双侧膈肌缺损男性中 CALN1 的从头缺失并不一定会导致这种畸形。

• DOI: 10.1002/ajmg.a.34002
• 发表时间: 2011
• 期刊: American journal of medical genetics. Part A
• 作者: Slavotinek,AnneM;Rosenfeld,JillA;Chao,Ryan;Niyazov,Dimitry;Eswara,Marthand;Bader,PatriciaI;Stockton,DavidW;Stankiewicz,Pawel;Adam,MargaretP
• 通讯作者: Adam,MargaretP

Two novel STRA6 mutations in a patient with anophthalmia and diaphragmatic eventration.

• DOI: 10.1002/ajmg.a.32682
• 发表时间: 2009-03
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: West, B.;Bove, K. E.;Slavotinek, A. M.
• 通讯作者: Slavotinek, A. M.

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.

• DOI: 10.1136/jmg.2011.089631
• 发表时间: 2011-06
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Slavotinek AM;Baranzini SE;Schanze D;Labelle-Dumais C;Short KM;Chao R;Yahyavi M;Bijlsma EK;Chu C;Musone S;Wheatley A;Kwok PY;Marles S;Fryns JP;Maga AM;Hassan MG;Gould DB;Madireddy L;Li C;Cox TC;Smyth I;Chudley AE;Zenker M
• 通讯作者: Zenker M

Novel FGFR2 deletion in a patient with Beare-Stevenson-like syndrome.

Beare-Stevenson 样综合征患者中出现新的 FGFR2 缺失。

• DOI: 10.1002/ajmg.a.32947
• 发表时间: 2009
• 期刊: American journal of medical genetics. Part A
• 作者: Slavotinek,Anne;Crawford,Howard;Golabi,Mahin;Tao,Cathy;Perry,Hazel;Oberoi,Sneha;Vargervik,Karin;Friez,Michael
• 通讯作者: Friez,Michael

Examination of FGFRL1 as a candidate gene for diaphragmatic defects at chromosome 4p16.3 shows that Fgfrl1 null mice have reduced expression of Tpm3, sarcomere genes and Lrtm1 in the diaphragm.

• DOI: 10.1007/s00439-009-0777-8
• 发表时间: 2010-03
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: LopezJimenez N;Gerber S;Popovici V;Mirza S;Copren K;Ta L;Shaw GM;Trueb B;Slavotinek AM
• 通讯作者: Slavotinek AM