Unlocking the Secrets of Complex Genomic Rearrangements in Disease

The human genome is a dynamic and ever-evolving puzzle shaped by various mutations and the forces of evolution. In a pair of recent studies, PNRI’s Carvalho Lab is making significant strides in unraveling the intricate relationship between our genes and their structure, shedding new light on the genetic underpinnings of specific diseases.

The first study, delves into a region of our genetic code implicated in at least three brain development disorders. This region overlaps with the MECP2 gene, a linchpin for normal brain function. However, some individuals are born with an extra copy of this gene, a condition known as MECP2 duplication syndrome (MDS), which can cause a range of neurological and developmental problems. Why MDS symptoms and their severity can vary so greatly among people with this condition has puzzled scientists and doctors for years.

The Carvalho Lab’s research uncovers a crucial aspect of this puzzle. They found that 30% to 50% of MDS DNA alterations exhibit complex genomic rearrangements, causing their DNA to deviate from the expected pattern. In their study of 137 individuals, they observed a wide spectrum of changes in this part of their DNA, varying from extremely small to quite large, which may impact many more genes than anticipated. Notably, the complexity of these DNA changes was closely linked to the severity of symptoms. More complicated rearrangements were associated with more severe problems, including overall survival and earlier onset of seizures.

What does this mean for our understanding of genetic disease? These findings challenge the conventional notion that the number of copies of the MECP2 gene solely determines disease severity. Furthermore, it highlights the pivotal role of the structural complexity of the genetic alterations in neurodevelopmental disorders.

“These studies challenge traditional beliefs, emphasizing the pivotal role of structural complexity in understanding genetic disorders, marking a significant leap in genetics research.”

Cláudia Carvalho, PhD
PNRI Assistant Investigator

In their second study, the Carvalho Lab investigated another complex genetic alteration. In this work, the team explored a complex genomic rearrangement known as the duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure in a group of 24 individuals with neurodevelopmental disorders. This genetic variation can lead to diseases, particularly when it involves important genes. 

Although rare, it has been identified in up to 26% of cases within certain disease groups, making it a substantial contributor to genetic disorders, common diseases, and cancer.  Despite its significance, scientists don’t fully understand the exact genetic structure when it occurs with previous predictions suggesting four potential sub-structures. 

Using cutting edge genomic methods not previously available, the team found evidence for all four predicted genetic patterns and pinpointed the precise location where genetic sequences combine to produce this genomic structure. Drawing on their findings, they developed a prediction model to understand how each of the four structures are formed. Understanding the nuanced differences between each DUP-TRP/INV-DUP structure may predict the severity of disease potentially impacting clinical care. Moreover, this study provides clues on regions prone to genomic instability in our genome which shed light on their formation and help to predict susceptibility regions. 

Both studies represent a critical step forward in genetics research. They shed light on the complex world of genomic rearrangements and their role in human disease. The Carvalho Lab’s work also underscores the crucial importance of delving deeper into unraveling the intricate mechanisms underlying genetic disorders and drives forward our understanding of complex genomic rearrangements in the development of genomic disorders.

The American Society of Human Genetics (ASHG) has recognized the significance of these findings, selecting PNRI’s Carvalho Lab for presentation at the prestigious ASHG 2023 Annual Meeting, where  pioneering research and innovative applications in all facets of human genetics take center stage.