PROJECT SUMMARY/ABSTRACT:
Congenital heart disease (CHD) presents a worldwide health burden as the most common type of congenital
abnormality, affecting ~1% of live births. While it remains the leading contributor to birth defect mortality, the
causes of CHD remain to be uncovered. Development of the heart is itself a complex process that is controlled
and regulated by multiple cell types, largely arising from the pharyngeal apparatus, a transient structure in
embryogenesis. The conotruncal region of the heart, composed of the outflow tract and great vessels, is
particularly susceptible to congenital anomalies since its formation and remodeling involve extensive
developmental processes. Conotruncal defects (CTDs) represent about 30% of all CHDs and occur in 40% of
patients with 22q11.2 deletion syndrome (22q11.2DS). TBX1, encoding a T-box transcription factor, is the main
causative gene for CTDs in 22q11.2DS, yet haploinsufficiency is not sufficient to explain the variable expressivity
of these defects. Therefore, 22q11.2DS represents a unique population in which to uncover genetic modifiers of
CTDs. To identify potentially damaging rare coding variants as modifiers, our lab performed whole genome
sequence analysis on 1,182 subjects with 22q11.2DS, with and without CHD. We found that chromatin regulatory
genes occurred in 8.5% of the 22q11.2DS subjects with CTDs. Some of these genes are also associated with
sporadic CHD in the general population, which is strongly suggestive that precise regulation of chromatin, and
consequently transcription, is essential for proper cardiac development. Our study aims to investigate the
interaction of chromatin regulatory genes, specifically Kmt2c and Kmt2d, with Tbx1 in mouse models. KMT2C
and KMT2D encode histone methyltransferases of the COMPASS family and they have also been implicated as
causative for sporadic CHD. I therefore hypothesize that Tbx1 and Kmt2c/d genetically interact in the
developmental processes critical for proper formation of the conotruncal region of the heart. To test this
interaction, I have generated mouse crosses for the conditional knockout of Kmt2c, Kmt2d, and Kmt2c/d in the
Tbx1 lineage. I will characterize cardiac defects through molecular and cellular approaches, as well as through
functional genomics studies that will delineate the shared and unique developmental roles of Kmt2c/d and Tbx1.
This will further the understanding of the genetic architecture of heart development and, consequently, the
etiology of CHD, knowledge of which will improve diagnosis and treatment.
