The human body shows left–right (LR) asymmetry of internal organs. Heterotaxy refers to discordance between asymmetry of different visceral organs, including the heart, lungs, liver, spleen, and stomach. It is highly variable, with major morbidity and mortality resulting from complex cardiovascular malformations. The estimates of heterotaxy occurrence range between 1 in 6,000– 20,000 live births; however, when spontaneous pregnancy terminations and stillbirths are taken into consideration, the occurrence is as high as 1 in 100, illustrating the importance of precise establishment of LR asymmetry for viable development. Most of our understanding in the determination of LR asymmetry results from studies in animal models.
We have recruited four consanguineous families, with multiple heterotaxy patients in each, displaying autosomal recessive inheritance in which we have excluded causative mutations in the Nodal and Shroom3 genes, known at the time. The goals of our proposal was to identify the mutations causing heterotaxia in these families and to study their mode of action.
our work was extremely fruitful in adding important information concerning the genetic causes of heterotaxy. Specifically, our findings identify an additional novel causative heterotaxy gene by identifying a mutation in the NME gene. In addition, our work contributes to the identification of a novel pathway involved in laterality by identification of a mutation in the MMP21 gene. Furthermore, we identified the CACNB gene as a potential heterotaxy gene. This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. This finding warrants further functional investigation. It should be noted that our data from the first two multiplex and the one simplex one, expandes the currently used NGS panel directed for heterotaxy and allows the use of prenatal diagnosis for heterotaxy associated with developmental and fatal complications in these families.
|Effective start/end date
|1/01/11 → …
- United States-Israel Binational Science Foundation (BSF)