Disorders of human morphogenesis are a major cause of human suffering for the affected individuals and their families. Congenital anomalies are identified in approximately 3% of term births, 10% of stillbirths, and in as many as 50% of first trimester spontaneous abortuses. While most, if not all, human structural birth defects have a significant genetic component, identification of genetic perturbations in isolated structural birth defects has been complicated by the complex nature of their underlying etiologies, likely involving disruption of regulatory elements that can act in a temporal and tissue specific manner, multi-gene, epigenetic and gene-environment interactions. Our approach to tease out genetic contributions to birth defects has been to identify the underlying causes of syndromic birth defects which are often Mendelian in nature and therefore lend themselves more readily to genetic causal identification. Once identified, these genetic causes of syndromic forms of birth defects can be leveraged to understand the genetic contributions to isolated birth defects seen in constellation in these syndromes. We propose to use Cornelia de Lange Syndrome (CdLS), a dominant multisystem developmental disorder consisting of a constellation of structural birth defects involving most body systems and significant growth and cognitive impairment as a prime example of this approach. We and others have shown that alterations in the cohesin and associated pathways are causative of CdLS and related diagnoses when disrupted and have more broadly been termed ?cohesinopathies? or ?disorders of transcriptional regulation (DTRs)?. In this proposal we outline an initial plan to analyze genome sequence and RNA sequencing data on a unique cohort of 400 probands and family members with clinically confirmed CdLS or a related diagnosis in whom molecular analysis by targeted gene sequencing, next generation sequencing (NGS) panels or exome sequencing have been negative, but are strongly suspected of having an underlying genetic alteration to explain their clinical features. This work will lead to the identification of genes critical in human embryonic development, provide novel insights into transcriptional regulation and help to identify genetic causes and candidate genes for isolated birth defects seen in constellation in this group of diagnoses. Most critical developmental genes are also cancer genes and the genes known to cause CdLS are no exception. CdLS is not a cancer predisposition syndrome so understanding the mutational mechanisms in these genes that lead to structural birth defects when present in the germ line and result in cancer when mutated somatically is a fundamental aspect of this research.
The proposed research Program is relevant to public health as we are addressing a major gap in our understanding of the genetic basis of syndromic and non-syndromic structural birth defects (with a focus on Cornelia de Lange syndrome and related diagnoses and birth defects), a major cause of human suffering for the affected individuals and their families. The proposed research Program is highly relevant to the NIH mission of improving health outcomes as we expect that discoveries of the basic mechanisms of structural birth defects will lead to improved diagnostics, counseling, management and therapeutics for affected individuals and their families.
