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.
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.
|Anger, Gregory J; Crocker, Susan; McKenzie, Kyle et al. (2014) X-linked deafness-2 (DFNX2) phenotype associated with a paracentric inversion upstream of POU3F4. Am J Audiol 23:1-6|
|Ordulu, Zehra; Wong, Kristen E; Currall, Benjamin B et al. (2014) Describing sequencing results of structural chromosome rearrangements with a suggested next-generation cytogenetic nomenclature. Am J Hum Genet 94:695-709|
|Hodge, J C; Mitchell, E; Pillalamarri, V et al. (2014) Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol Psychiatry 19:368-79|
|Sugathan, Aarathi; Biagioli, Marta; Golzio, Christelle et al. (2014) CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc Natl Acad Sci U S A 111:E4468-77|
|Romeike, Bernd F M; Shen, Yiping; Nishimoto, Hiromi Koso et al. (2014) Spectrum of genes involved in a unique case of Potocki Schaffer syndrome with a large chromosome 11 deletion. Clin Neuropathol 33:238-44|
|Gfrerer, Lisa; Shubinets, Valeriy; Hoyos, Tatiana et al. (2014) Functional analysis of SPECC1L in craniofacial development and oblique facial cleft pathogenesis. Plast Reconstr Surg 134:748-59|
|Talkowski, Michael E; Minikel, Eric Vallabh; Gusella, James F (2014) Autism spectrum disorder genetics: diverse genes with diverse clinical outcomes. Harv Rev Psychiatry 22:65-75|
|Chen, Xiaoli; Shen, Yiping; Zhang, Feng et al. (2013) Molecular analysis of a deletion hotspot in the NRXN1 region reveals the involvement of short inverted repeats in deletion CNVs. Am J Hum Genet 92:375-86|
|Lindgren, Amelia M; Hoyos, Tatiana; Talkowski, Michael E et al. (2013) Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. Hum Genet 132:537-52|
|Beunders, Gea; Voorhoeve, Els; Golzio, Christelle et al. (2013) Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet 92:210-20|
Showing the most recent 10 out of 44 publications