To achieve our overall goal of identifying genes important in human development, Project 1 (High Throughput FISH Mapping) will map chromosomal breakpoints from individuals with apparently balanced rearrangements and congenital anomalies. We hypothesize that chromosomal rearrangements in these individuals are responsible for the abnormal phenotypes, either through haploinsufficiency or some other genetic mechanism(s). Study subjects will be identified and enrolled through our growing international network of clinical geneticists, genetic counselors, and clinical cytogeneticists, and from the NIGMS Human Genetic Cell Repository. Peripheral lymphocytes or fibroblast specimens will be obtained from consented research subjects, and lymphocytes will be immortalized to provide ongoing sources of cellular material for our studies. Participants have the option of granting permission for us to contribute aliquots of these samples to the NIGMS Human Genetic Cell Repository, through which they can be shared anonymously with the entire scientific community. Prior to intensive breakpoint mapping, we will use array comparative genomic hybridization (aCGH) technology to detect cryptic or submicroscopic changes that could potentially confound subsequent analyses, and further analysis of cases with significant deletions or evidence of complex rearrangements would be deferred. According to our existing prioritization criteria, 12 cases/year will be selected for high-resolution breakpoint mapping by FISH using fully or end-sequenced BAG and fosmid clones. The case selection criteria favor cases with a higher likelihood that a given chromosomal rearrangement is responsible for the abnormal phenotype and take advantage of the particular expertise of DGAP Investigators in diverse areas of developmental pathobiology. Breakpoint mapping will be enhanced by FISH performed on naked DMA fibers (i.e., fiber FISH) instead of metaphase chromosomes in selected cases, particularly those with segmental duplications. Such detailed mapping studies are the entry point for the identification and characterization of developmental^ important gene(s) (Project 2), as well as the generation of animal models (Project 3). Project 1 laboratories will lead the gene discovery, functional analysis, and validation of candidate genes in DGAP cases involving female genital tract disorders and hearing loss. Finally, Project 1 will continue to share DGAP results via the Internet (http://dqap.harvard.edu/) in keeping with our goal of being a karyotypephenotype resource for clinical geneticists, cytogeneticists, and developmental biologists worldwide. In summary, Project 1 will serve as the entry point for a functional genomics project generating a public resource of genes critical to human development.

Public Health Relevance

The Developmental Genome Anatomy Project studies a group of patients underserved by the health care system: those with congenital abnormalities due to chromosome rearrangements. Our mission is to discover genes of importance in human development that are disrupted by these chromosomal rearrangements, genes that are difficult to identify by more traditional human genetic strategies, thereby opening investigation of the disorders that they cause.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM061354-09
Application #
8377566
Study Section
Special Emphasis Panel (ZRG1-GGG-G)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$491,778
Indirect Cost
$139,599
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Zepeda-Mendoza, Cinthya J; Ibn-Salem, Jonas; Kammin, Tammy et al. (2017) Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements. Am J Hum Genet 101:206-217
Redin, Claire; Brand, Harrison; Collins, Ryan L et al. (2017) The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Nat Genet 49:36-45
Dong, Zirui; Wang, Huilin; Chen, Haixiao et al. (2017) Identification of balanced chromosomal rearrangements previously unknown among participants in the 1000 Genomes Project: implications for interpretation of structural variation in genomes and the future of clinical cytogenetics. Genet Med :
Cretu Stancu, Mircea; van Roosmalen, Markus J; Renkens, Ivo et al. (2017) Mapping and phasing of structural variation in patient genomes using nanopore sequencing. Nat Commun 8:1326
Chen, Xiaoli; An, Yu; Gao, Yonghui et al. (2017) Rare Deleterious PARD3 Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation. Hum Mutat 38:378-389
Schilit, Samantha L P; Morton, Cynthia C (2017) 3C-PCR: a novel proximity ligation-based approach to phase chromosomal rearrangement breakpoints with distal allelic variants. Hum Genet :
Xie, Hua; Li, Xiaoyan; Peng, Jiping et al. (2017) A complex intragenic rearrangement of ERCC8 in Chinese siblings with Cockayne syndrome. Sci Rep 7:44271
Loviglio, M N; Leleu, M; Männik, K et al. (2017) Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes. Mol Psychiatry 22:836-849
Lohmann, Katja; Redin, Claire; Tönnies, Holger et al. (2017) Complex and Dynamic Chromosomal Rearrangements in a Family With Seemingly Non-Mendelian Inheritance of Dopa-Responsive Dystonia. JAMA Neurol 74:806-812
Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248

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