'Genotype-first' approach could fine-tune diagnosis of genetic disorders

Illustration of three DNA helices
Cold Spring Harbor's Gholson Lyon expects many more disorders caused by rare mutations to be discovered. (Darwin Laganzon)

An international group of scientists started with a genetic mutation and tracked down people who had it, finding 37 individuals with an NAA15 mutation and a multitude of symptoms. Instead of starting with a collection of symptoms and then casting about for their cause, this "genotype-first" method could fine-tune diagnoses and help researchers devise treatments for genetic disease, they believe. 

It all started with Ogden syndrome, a serious condition that shares many of the symptoms related to the NAA15 mutation. The team, led by Gholson Lyon of Cold Spring Harbor Laboratory, discovered Ogden syndrome, which is caused by a related gene, NAA10, in 2011.

Since then, Lyon's team sought information about individuals with a mutation in the NAA15 gene, which codes for NatA-mediated N-terminal acetylation, a protein that works with the NAA10 protein in a cellular process that modifies other proteins. 

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They found 37 men and women and 32 families with an NAA15 mutation. They had a wide range of symptoms, including intellectual disability, developmental delay, autism spectrum disorder, abnormal facial features, seizures and congenital cardiac anomalies. The findings are published in the American Journal of Human Genetics 

"Trying to prove the relevance of any mutation in a gene requires a large number of samples," Lyon said in a statement. As genetic sequencing becomes cheaper and more accessible, "we may be able to provide individuals with such mutations with more education and services in early life which could lead to better overall functioning," he said. 

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Identifying what Lyon calls "NAA15-related disorder" is just the tip of the iceberg—he expects more disorders caused by rare mutations to be discovered using this method. 

"Instead of lumping many diseases together under very broad categories like 'intellectual disability' or 'autism,' the human genetics community is now splitting these into much finer entities so that we can begin to do natural history studies, much like what has been done with Fragile X syndrome," he said, referring to progress that has been made in that disease by performing extensive examinations of mutations in the FMR1 gene. FMR1 codes for a protein called FMRP, which helps regulate the production of other proteins and is involved in the development of synapses. 

Researchers from Washington University in St. Louis and Emory University studied sequencing data from 900 patients with some common intellectual disabilities, but without the whole complement of symptoms used to diagnose Fragile X. They found one patient with a single error in the FMR1 gene and two Fragile X symptoms: intellectual disability and seizures. 

"This individual case has allowed us to separate two independent functions of the Fragile X protein in the brain," said co-senior author Vitaly Klyachko, associate professor of cell biology and physiology at Washington University, at the time. "By finding the mutation, even in just one patient, and linking it to a partial set of traits, we have identified a distinct function that this gene is responsible for and that is likely impaired in all people with Fragile X."