# Genomic Diagnostics in Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects

> **NIH NIH R03** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $176,000

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 9991879
- **Project number:** 5R03HD099530-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** IAN D. KRANTZ
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $176,000
- **Award type:** 5
- **Project period:** 2019-08-09 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991879

## Citation

> US National Institutes of Health, RePORTER application 9991879, Genomic Diagnostics in Cornelia de Lange Syndrome, Related Diagnosis and Structural Birth Defects (5R03HD099530-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9991879. Licensed CC0.

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