insight into the pathogenesis of human vesico-ureteral reflux, or VUR. In addition, several novel clefting loci were identified which suggest new molecular mechanisms for palatal craniofacial development. Lastly, we identified a novel component of the mammalian RNA processing or P-body that regulates lens formation. These results confirm the power of this approach to establish causality for DGAP candidate genes. In the next grant period, we will extend this functional genomics approach and pursue more in-depth phenotype analyses. Furthermore, targeted mutations in most mouse genes will likely be attained during the next grant period. Therefore, the emphasis of Project 3 will now begin to shift from preparing conventional null alleles for DGAP candidate genes to making use of existing mouse models, preparing conditional alleles where required, and to pursuing more detailed phenotype analyses.
In Aim 1, we will pursue new mouse mutational technology that is higher throughput than conventional gene targeting. Alternatively, in select cases, we will undertake a morpholino knockdown approach in zebrafish.
In Aim 2, we will conduct marker gene experiments, genetic intercrosses and molecular experiments to establish causation, place genes into evolving pathways and identify the relevant developmental mechanisms. The overall goals of Project 3 continue and will be expanded in the future. The successful approach remains to delineate the developmental functions of new genes, and to provide definitive proof that mutations in these human genes produce birth defects.

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. PROJECT/

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-G)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
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