Genetic Interactions That Cause Cornelia de Lange Syndrome Could Offer Clues on the Origins of Several Types of Birth Defects

A new study has offered new insights into the secret origins of birth defects, unlocking new avenues of exploration for early detection and prevention strategies.

Prevalence of Birth Defects

Every year, about 3% of babies in the US are born with a birth defect. These structural changes can affect almost any part of the body, the most prevalent of which are neural tube defects, congenital heart defects, and cleft lip/palate.

Early detection of and intervention for birth defects can improve life outcomes and reduce long-term health care costs. For this reason, there is a need to explore the origins of birth defects, given the major impact that they have on infant mortality and morbidity. However, their diversity and sporadic nature pose challenges for identifying causal mechanisms.

One example of multiple congenital anomalies is Cornelia de Lange syndrome (CdLS), a rare genetic disorder characterized by prenatal and postnatal growth deficiency, distinctive facial appearance, psychomotor delay, feeding difficulties, associated malformations, and behavioral problems. It affects approximately 1 in 10,000 to 1 in 30,000 live births.

Almost 55% of CdLS are caused by heterozygous mutations in the gene Nipped-B-like (NIPBL) which usually produce a nonfunctional protein. This suggests that precise gene dosage of NIPBL is important in human development.

Unlocking the Mysterious Origins

At the University of California, Irvine, researchers made a profound discovery concerning NIPBL and its intricare connection with another gene, Nanog. This protein coding gene is mainly involved in inner cell mass and embryonic stem cells proliferation and self-renewal.

The study is led by Stephenson Chea from the Department of Developmental and Cell Biology. The details of this research are discussed in the paper "Gastrulation-stage gene expression in Nipbl+/- mouse embryos foreshadows the development of syndromic birth defects".

The data gathered by the research team suggests that NIPBL and Nanog are not only important in early embryonic development. They are actually critical regulators which, when misregulated together, can have far-reaching effects on embryogenesis and the development of many tissues and organs.

This crucial venture started with a cutting-edge approach to mapping gene expression in early embryonic cells. The researchers explored the gene expression profile of every cell population present during a foundational stage of development known as gastrulation. This was made possible by employing single-cell RNA sequencing and innovative bioinformatic strategies.

The team discovered differences in gene expression and cell population sizes between normal embryos and those that were NIPBL-deficient. This finding offered unprecedented insights into the earliest origins of birth defects.

According to research co-author Anne Calof, this is the first time for this complex developmental syndrome that experts have been able to unlock such profound gene expression differences at an important developmental juncture. This led them to believe that they are finally beginning to understand a fundamental aspect of the mechanism in which congenital birth defects appear during early development.

Understanding the precise timing in developmental pathways introduces the possibility of medical interventions. Furthermore, it also opens a window for identification of biomarkers which could play an important role in developing therapeutic interventions.