Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.

This week’s study is…

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

We previously published about this research in a story titled “Research Explores Two Genes Linked to Microcephaly” which can be found here. The study was originally published in the scientific journal Nature Communications. You can read the full text of the study here. 

This research team was affiliated with Northwestern University.

What Happened?

Microcephaly is a medical condition characterized by abnormally small head size. It has been linked to an interruption of the processes related to brain development during pregnancy. In this study, a team of researchers sought to understand the genetic basis of microcephaly more clearly by seeking to identify specific genes associated with its appearance. The team identified two genes that were linked to the condition when certain disease-causing DNA variants were present.

To conduct this study, the scientists looked at whole exome sequencing data from 11 people affected by a syndrome of microcephaly, short stature, anemia, and heart abnormalities. The researchers dubbed this collection of symptoms “Atelís syndrome.” They identified DNA variants in the SMC5 and SLF2 genes that could reduce the ability of cells to repair DNA damage and harmed protein stability. In order to specifically link these variants to the development of microcephaly, the researchers utilized a zebrafish model.

The zebrafish (Danio rerio) is a small freshwater fish native to South Asia. While at first a small fish may not seem like a useful model for human research, zebrafish are easy to raise in captivity, has a fully sequenced genome, readily observable developmental behaviors, consistent size in early development, remarkable similarities to mammals in toxicity tests, and regenerative abilities.

The team inactivated SMC5 and SLF2 in the genome of the zebrafish and found that in the fish that had been altered, their heads were smaller than in unaltered fish. 

About Microcephaly

Microcephaly is a condition in which the brain does not develop properly in the womb, which leads to abnormally small head size. It is often present at birth, but in other cases it may develop in the first few years of a person’s life. There are many different genetic abnormalities and syndromes that can cause it, and it can also be acquired. Risk factors include infection of the mother with Zika virus and consumption of alcohol during pregnancy. Symptoms include intellectual disability, mobility problems, dwarfism, seizures, and poor speech. A small number of people with mild microcephaly may develop normal intelligence. While mutations that solely cause microcephaly do exist, it is more common for it to appear alongside other signs and symptoms. There is no cure for microcephaly and treatment is supportive and based on the symptoms present. To learn more about this condition, click here. 

Why Does it Matter?

The scientists were able to successfully identify two new genes associated with microcephaly, which will be an important asset in early detection. The scientists recommend that SMC5 and SLF2 genes be added to sequencing and gene panel tests for microcephaly in the future. The team also highlights that these discoveries provide clues about future research directions as well:

“It’s also informing us about groups of proteins that perform a similar function in the cell, the RAD18-SLF1/2-SMC5/6 complex.” – Erica Davis, Ph.D., associate professor, Pediatrics and of Cell and Developmental Biology, co-senior study author

It’s clear that these genes are important for the stability of the genome. They also play a role in cell division and DNA replication. Davis’s lab has taken a special interest in ultra-rare inherited disorders:

“The first pillar of that is identifying the causal genes, the second is understanding the mechanism and the third is therapeutic development. As we develop these zebrafish models, this gives us a new tool to try to identify ways to correct a cellular process that’s gone wrong.”