One to two out of every 100 newborn babies are born with a Congenital Heart Defect (CHD), yet the exact cause remains unclear. Human geneticists at the University Medicine Oldenburg (Germany) have now presented a new method for determining whether a NOTCH1 gene variant is causative. Once they know this, doctors will be able to make more reliable diagnoses and develop targeted and effective therapies. In addition, patients and their families will finally be able find out whether a heart defect is likely to be hereditary. A team led by Professor Dr Marc-Phillip Hitz, Director of the University Institute for Medical Genetics at the Klinikum Oldenburg, and Dr Gregor Dombrowsky, the first author of the study, reported its findings in Genome Medicine.
Pinpointing the exact cause of a congenital heart defect is often like looking for a needle in a haystack. Humans have approximately 20,000 genes, and each gene can carry different variants, some of which have negative effects. In many cases, heart defects are caused by multiple genetic alterations that occur simultaneously. In short, the number of potential combinations is vast.
Oldenburg researchers have now provided new insights by conducting molecular genetic analyses of blood samples from almost 4,000 children with heart disease. One particular gene kept cropping up in their study: NOTCH1, which encodes an important signalling protein that plays a key role in determining how an embryo's heart develops. If the blueprint is altered, the resulting signalling protein malfunctions and disrupts the highly complex molecular genetic process of embryonic heart development. This small change leads to a cascade of errors with far-reaching consequences, such as congenital heart defects. Although NOTCH1 variants account for only 1% of all congenital heart defects, this gene is the most common monogenic cause of such defects.
"Some variants of this gene were already known to cause congenital heart defects, partly because other causes could be ruled out. In practice, however, we encounter a large number of NOTCH1 variants, some of which are new, and we don't yet know whether they are harmless or causative," explains Dombrowsky. "So we looked for a way to determine this in these cases, too."
Like detectives in a crime thriller, the researchers followed the trail left by well-researched and severe NOTCH1 variants in the DNA of affected individuals. They knew that the disruption in the signalling process caused by the genetic defect ultimately leads to other genes that are otherwise completely intact not being correctly transcribed. Methyl groups attach to various locations in DNA, a process known as methylation. The researchers suspect that methylation patterns are altered in affected individuals.
The Oldenburg researchers discovered that, across subjects with different NOTCH1 variants, the same genomic segments were consistently affected by altered methylation. "This pattern of affected DNA segments is like a fingerprint left by a single pathogenic NOTCH1 variant in the genome. This knowledge can now be used to reliably diagnose whether a variant is the cause of a heart defect," Dombrowsky explains.
