The Sequence 8/21-8/27
Inherited Variants May Have Link to Autism, Population Genetic Testing, Spectrum of Genes Associated with ALS in Chinese Population, Childhood Psychosis Linked to Deletions and Duplications in the DNA
Inherited variants may have greater link to risk for autism than previously thought
Approximately 100 autism genes have been identified to date. When I say that, I mean ~100 causative autism genes; i.e., a mutation, or a harmful change, in one of those genes will cause autism. On its own.
However, it is expected that more like ~1,000 genes contribute to autism.; i.e. mutations in multiples of these genes likely work together in a unique way to cause autism. That would make one of these thousand or so genes on its own just a risk factor, and not a cause by itself. That’s where this study comes in.
How?
Chung et al. analyzed the DNA sequence of 42,607 autism cases in order to identify new genes associated with autism. They ended up identifying 60 risk genes for autism, including 5 new genes that were never associated with autism before.
What’s more? The study found that rare inherited mutations (i.e. mutations passed down from a parent) are just as likely to be risk factors as mutations that are de novo (i.e. random and definitely NOT inherited from a parent). This is huge, because in the past, studies have focused on rare de novo variants to identify genes associated with autism. And if you think about it, this makes sense- if mom and dad have no history of autism but their child does, it sounds like it shouldn’t be inherited, right?
Well, it’s a lot more complicated than that… and in fact the study predicts that a cohort of 52,000 - 227,000 cases are actually needed to find all of the risk genes involved in autism. Big data, here we come.
Are we ready for population genetic testing?
Population genetic testing is performing genetic testing on the entire population, not just people at a higher risk of a genetic disorder.
Why would we do that?
Population genetic testing can detect people at risk for common disorders with known genetic risk factors, such as various cancers and heart diseases, at a younger age. This can decrease the age at which individuals are seeking the appropriate preventative care, such as screening for breast cancer at an earlier age in an individual with a BRCA1 or BRCA2 mutation. Population genetic testing (aka population genetic screening) may help people avoid serious diseases and death, which is a worthy goal for patients, employers, payers and our population at large.
Cool! Why aren’t we doing it yet?
In this article by Ellen Matloff, she outlines some great reasons. To be honest, most of them are systemic: if we begin population screening, we also need to be ready with enough resources to handle the results. For example, we need enough genetic counselors to meet with patients to interpret and explain the results, we need the support of employers to offer PTO to cover preventative screening (e.g. breast MRIs for individuals with an increased risk for breast cancer, to use the example above), and the support by insurance companies to cover the cost of that screening.
Essentially, we just might not be there yet.
Spectrum of genes associated with ALS identified in Chinese population
Chen et al. analyzed the DNA of 1,600 individuals from mainland China with amyotrophic lateral sclerosis (ALS) in order to understand the genetic spectrum of ALS.
What is ALS?
ALS is is a progressive disease that affects motor neurons, which are specialized nerve cells that control muscle movement. Since motor neurons die (atrophy) over time, individuals with ALS eventually experience muscle weakness, loss of muscle mass, an inability to control movement, and eventually lose the ability to walk. About 5-10% of people with ALS have a family history, however most have no family history (aka sporadic). Most people first develop features of ALS in their late fifties or early sixties.
What do you mean they studied the ‘genetic spectrum’ of ALS?
Some ALS is caused by genetic mutations, harmful changes in the DNA. In fact, we know ~120 genes that can cause ALS. Understanding the ‘genetic spectrum’ refers to understanding which genes might cause more severe or more early onset-disease (aka genotype-phenotype correlation).
Before this study, we didn’t know this genotype-phenotype correlation in the Chinese population, as the majority of these studies have been performed in the European population.
So what did they find?
First off, genetic mutations causing ALS were identified in ~25% of the cohort of 1,600 patients (FYI that’s considered a high diagnostic rate these days). Specifically, mutations were identified in ~41% of patients with a family history, and and in ~9% of patients with no family history. Makes sense.
They then went as far as to recommend which genes should be tested for in the Chinese population based on which genes were identified most frequently. Finally, they commented on the genotype-phenotype correlation of certain ALS genes: patients with mutations in the SOD1 gene tended to first involve lower limb weakness, mutations in the FUS and TARDBP genes were associated with an earlier age of onset and faster progression, and mutations in the NEK1 and ANXA11 genes were associated with later age of onset and slower progression.
Is any of this different from what we already knew?
Yes! The biggest contrasting finding to other studies looking at the genes involved in ALS, again using mostly European samples, was the top gene involved! While in past studies, the top gene causing ALS is C9ORF72, it was SOD1 in this cohort of individuals from China.
What’s the takeaway here?
We’re not all the same, and so the genetic testing offered to us all should not be the same either. This study supports focusing on different genes that cause ALS in individuals with Chinese background.
Childhood psychosis linked to deletions and duplications in the DNA
Brownstein et al., a group based from Boston Children's Hospital, studied children with psychosis, i.e. they suffer from a disruption in thinking that can cause hallucinations and bring in to question what is real and not real, to identify whether small deletions and duplications in the DNA may put children at increased risk for psychosis.
What are these small deletions and duplications in the DNA?
Small deletions and duplications in the DNA, also called copy number variations, or CNVs, are entire sections of letters that are extra or missing. It could be a hundred letters, it could be a thousand letters, it could be THOUSANDS of letters. These CNVs can be only a piece of a gene, or they could encompass many genes, depending on how small or big the CNV is.
The results?
The group identified CNVs in ~40% of the cohort of 137 children with early-onset psychosis.
Is any of this different from what we already knew?
Yes! Past studies have linked CNVs to psychosis in adults, but psychosis onset in individuals under 18 (specifically presenting from 4 and 17 years old) had not been studied.
What’s the takeaway here?
Testing for CNVs (the test is called a microarray) should be considered in children with psychosis.