Gabriella Miller Kids First Pediatric Research Project in Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects

This study involves a cohort of 400 individuals and family members with Cornelia de Lange Syndrome (CdLS) and CdLS-like phenotypes for which a molecular etiology has not yet been established. CdLS is a developmental disorder characterized by development delays, cognitive impairment, short stature, hearing loss, specific facial features, and structural birth defects such as differences of the limbs, heart, kidneys, and GI tract. 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 syndromes such as CdLS. 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 similar diagnoses. ]]>
400 samples (288 trio samples, 60 duo samples, and 52 singletons) were selected for genome sequencing as part of the Gabriella Miller Kids First Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects project. DNA extracted from whole blood or LCLs for probands with CdLS and CdLS-like phenotypes along with DNA from the proband's mother and/or father make up each trio and duo. The study subjects have been collected as part of the CdLS and Related Diagnoses research project at the Children's Hospital of Philadelphia. ]]>
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. 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, is used 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 order to understand the etiology of these cohesinopathies, investigators from the Children's Hospital of Philadelphia have recruited large numbers of CdLS and related cases across the country and the world over the course of many years of collaborative studies.

For the current Kids First project, genome sequencing will be performed on 400 samples (inclusive of 288 trios, 60 duos, and 52 singletons). Probands have clinically confirmed CdLS or a related diagnosis where molecular analysis has been negative thus far but are strongly suspected of having an underlying genetic alteration to explain their clinical features.]]>