Congenital Malformations


Congenital Malformations - Ten Year Vision

Congenital malformation research will be transformed by the combination of 1) next generation human genomics and 2) functional analysis of candidate genes in model systems. In order to lead this revolution, we need to create a translational infrastructure that enrolls congenital malformations patients into genomics analyses, identifies candidate genes, and then tests those candidate genes in model systems for functional relevance. Once functional relevance is established, then deep mechanistic studies can discover the underlying developmental role. Such a research program has the following long term aims:

Radiograph of normal and heterotaxic anatomy

1. Create a congenital malformation genetic test

We anticipate that human genomics will continue to advance making disease causing variant detection cheaper and more accurate. Currently, both a genetic and a gene functional approach are necessary for annotating genes as disease causing. The culmination of this work will define a set of genes that cause congenital malformations. Sequencing these genes will then become the basis for genetic testing. While genetic testing will provide many answers to parents and clinicians, by coupling genetic testing with clinical follow-up and functional analysis, we also hope to develop prognostic and therapeutic strategies by personalizing medicine towards the underlying genetic disorder rather than simply phenotype.

2. Understand our own construction

A surprising result of the congenital heart disease genomics is that most of the candidate genes identified do not fall into known pathways of cardiac development. We anticipate that other congenital malformations will be similar. We believe this reflects our superficial understanding of development. Therefore, congenital malformation research has the potential to be an extraordinary gene discovery platform for developmental biology. Coupled with model system analysis, congenital malformation research will identify new mechanisms of development and dramatically improve our understanding of our own construction.

To achieve these goals, there are Immediate Needs:

1. We must phenotype, record, and collect DNA samples from congenital malformation patients, their parents, and ideally, an unaffected sibling.

It is essential that we begin this now and collect all patients. First, extraordinary biology can be discovered from a single patient so a comprehensive collection of all phenotypes is essential. Second, initially, we anticipate that collections may outpace sequencing given current costs. However, with the current pace of sequencing advances, costs will surely fall at which point whichever group has samples for sequencing will be at a marked advantage over those that are simply initiating collections. Clearly the currency of future human genetic work will be available samples.

2. We must create a collaborative environment to collect, analyze, and functionally characterize the candidate genes identified in congenital malformations patients.

This collaboration must start between clinicians, geneticists, and developmental biologists, groups which are unaccustomed to working together but which are essential to make headway on congenital malformation research. Another surprising finding in our preliminary studies is that the congenital malformation genes span many disciplines across biology. So while clinicians, geneticists, and developmental biologists are necessary for the preliminary characterization of candidate genes, for a deep mechanistic understanding, we will need the collaborative effort of disparate fields of biology.