The Sequence 11/21-11/27
Poor Neurodevelopmental Outcomes and Epigenetic Aging, Myriad Will Submit Data Publicly, A New Way to Assess for Autosomal Recessive Conditions, Utility of Polygenic Risk Scores in Breast Cancer
Poor neurodevelopmental outcomes are associated with advanced epigenetic aging
Gomaa et al. studied epigenetic aging in 35 very preterm infants to see whether epigenetic age may explain poor neurodevelopmental outcomes in these babies (because we know that prematurity is not necessarily always correlated to poor neurodevelopmental outcomes).
Epigenetic what?
Epigenetics is the study of how the environment can cause changes that affect the way genes work.
It goes like this: Our DNA is made up of genes, and those genes are made up of a string of letters that act as a code, or like an alphabet, that tells our bodies how to grow and develop. While usually in genetics we are talking about conditions being caused from changes in those letters, called pathogenic genetic variants or mutations, epigenetics is talking about conditions being caused from the genetic code being activated or silenced. Epigenetic changes affect gene expression to turn genes “on” and “off”.
Epigenetic aging, then, is aging caused by the expression or silencing of certain genes. It’s already established that epigenetics change throughout your life, and that your epigenetics at birth is not the same as your epigenetics during childhood or adulthood.
So the group was looking for epigenetic sign of aging in newborns?
Yes. And they found it, using the pediatric buccal epigenetic (PedBE) clock —a recently developed tool to measure biological aging. It works by looking at the DNA expression 94 different age-informative sites in the DNA, which accurately estimate chronological age among normative, healthy, and full-term children.
Cool. What did they find?
Among the 35 preterm infants studied, the 23 that were born extremely preterm (<28 weeks’ gestation), had an accelerated PedBE age compared with the others.
They also found that the accelerated PedBE age was associated with significantly smaller brain volumes and slower brain growth and lower cognitive and language scores at 18 months.
What’s the takeaway?
This study suggests that increased epigenetic biological aging may be associated with decreased neurodevelopmental outcomes. There’s certainly more studies to be done in this area of research, with larger numbers of babies studied in the future.
Myriad will submit data publicly beginning in 2023
In the genetics community, Myriad is associated with an infamous case regarding the Surpreme Court’s ruling in favor of protecting from private companies being able to patent genes. See more about this in this post.
Now, the company has recently announced they will be submitting genetic variants identified from their testing into a public database called Clinvar. This is surprising and exciting news coming from the company who wanted to patent genes.
Interesting! Tell me more.
Myriad was the first major clinical genetic testing lab to test patients for BRCA1 and BRCA2 mutations (i.e. harmful changes in the DNA). BRCA1 and BRCA2 mutations are the most well known genetic causes of Hereditary Breast and Ovarian Cancer Syndrome. They first began testing patients way back in 1996. As such, they have collected a ton of information about variation in BRCA1 and BRCA2. With so much data, they have more information on which BRCA1 and BRCA2 variants are pathogenic (i.e. disease causing) mutations, versus which variants are benign, than anyone else in the industry. Once Myriad shares its data in a way that other clinical labs will have access, the overall interpretation of genetic variation in the BRCA1 and BRCA2 genes will become more accurate, helping for more clinically relevant interpretation and diagnosis of mutations in BRCA1 and BRCA2.
That’s great!
It is. Myriad has changed its tune on data-sharing in the last decade, to the delight of healthcare providers and researchers in the field alike. Let’s hope this is one step toward a future of data-sharing for the greater utility of genetic testing in the future.
A new way to assess for autosomal recessive genetic conditions
Yuan et al. worked to understand a new way to discover genes associated with autosomal recessive conditions.
As a review, an autosomal recessive condition is a condition in which individuals need two non-working copies of a gene (i.e. mutations in both copies of the same gene) to have the disorder.
What’s the new way to assess for these conditions?
The study team wanted to assess whether an increase in nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions increases the chances of mutations for autosomal recessive conditions.
Let’s break that down. When your cells are splitting themselves to create sex cells, i.e. eggs in women and sperm in men, the like, or ‘homologous’ chromosomes line up next to each other before splitting. In this moment, ‘recombination’ occurs, meaning the two chromosomes swap pieces of DNA. In nonallelic homologous recombination (NAHR), this DNA swapping, or recombination, happens at a part of the DNA where it’s not supposed to. So we can think of the term nonallelic homologous recombination (NAHR) as ‘DNA swapping but not at the right spot’.
Now for the next part: NAHR-mediated recurrent genomic deletions. Think of this as NAHR causing deletions in the DNA (because the swap happened at the wrong spot and things are no longer lined up).
So, is this unaligned DNA swapping associated with an increase in autosomal recessive conditions?
Yes! Important, because while identifying genes that cause autosomal dominant conditions, or genetic conditions caused by one gene mutation in one copy of a certain gene, is straightforward, identifying genes that cause autosomal recessive conditions has not been easy. Now that we know NAHR-mediated recurrent genomic deletions is associated with an increase in autosomal recessive disease genes, we can spot these genes by spotting the NAHR. With the discovery of more autosomal recessive disease genes, an increasing amount of people can be diagnosed and informed of their genetic conditions earlier in life.
Thanks for bearing with me on this one.
The utility of polygenic risk scores in predicting familial breast cancer
A study by Lakeman et al. examined data on more than 3,918 participants with a family history of breast cancer to evaluate the accuracy of polygenic risk scores in predicting familial breast cancer.
What is a polygenic risk score?
A polygenic risk score (PRS) is a number, or a ‘score’ that estimates an individual’s risk for a certain condition. They are used in conditions that are caused by changes in many genes, often coupled with environmental factors.
How are they determined?
Let’s use breast cancer as an example, because that is the health outcome studied in this article. Scientists created PRSs for breast cancer by comparing the DNA of patients with and without breast cancer to determine a ‘collection of genes’ that have more rare variation in the individuals with breast cancer that are not there in the individuals without breast cancer. Then, they can say if you have these ‘X’ number of genes, your PRS for breast cancer is increased.
What did they find?
The group did in fact find that genetically predicted risk for breast cancer (i.e. based on a high PRS) added clinical value to the prediction of breast cancer in addition to predictive scores based on family history. When using PRS in addition to family history-based risk prediction on women with a family history of breast cancer, screening recommendations changed in up to 34% of individuals.
What's the takeaway?
The implementation of PRSs in addition to risk assessment based on family history may have significant impact on clinical management for women with a family history of breast cancer.