Why Some People With Disease-Causing Gene Mutations Never Get Sick

A growing body of research is overturning the long-held assumption that disease-causing genetic variants inevitably lead to disease. Studies have found that in fact the majority of people with mutations linked to rare, inherited eye diseases were just fine—only a small number actually developed eye disease, according to researchers at Mass General Brigham hospital. This phenomenon, known as penetrance, means the landscape of so-called single-gene disorders is far more complex than anyone realized.

When geneticists first began searching for the genes responsible for various inherited diseases in the 1970s and 80s, they worked backwards, starting with large families impacted by often devastating conditions. The strategy was slow and painstaking, but undoubtedly successful as geneticists identified the cause of everything from cystic fibrosis to Huntington's disease to retinitis pigmentosa. But the model had a baked-in bias: because it was so laborious and expensive, scientists only sequenced the DNA of 'the sickest of the sick,' which led to inflated statistics of what it meant to have these genetic changes.

This began to change in the wake of the Human Genome Project. Researchers have begun to investigate the biological reasons why someone stays healthy, which may help reshape our fundamental understanding of biology and inheritance, as well as develop new treatments for some of our deadliest diseases. 'This whole paradigm that we had, of variant A causes disease B almost all the time, is actually not the norm,' said Leigh Jackson, a geneticist at the University of Exeter in the U.K.

The hope of such studies is to identify 'modifier' genes within the human genome that can be manipulated to mitigate or cancel out genetic conditions. Marfan syndrome is particularly mysterious because members of a family who carry the same exact mutation can have wildly different health trajectories, said Catherine Boileau, a geneticist at the French health research institution INSERM. Within a given family, the disease can appear at very different ages and with starkly different severity.

Boileau knows from experience that finding modifier genes can pave the way to lifesaving therapies. She was involved in early research into a gene called PCSK9: Mutations that lower the gene's activity can avert sky-high cholesterol levels usually caused by inherited errors in another gene. That discovery helped create a class of drugs that mimic the effects of disabling PCSK9.

Modifier genes also have a role in sickle cell disease, one of the most common inherited disorders in the world. Scientists identified genetic mutations causing sickle cell disease decades ago, but around the mid-2000s, they began discovering modifier genes, including one that could help jump-start hemoglobin production. One of the very first gene-editing therapies that the FDA approved for sickle cell disease works precisely by shutting down this modifier gene.

In recent years, more scientific groups have been identifying genetic outliers who might possess helpful variants of modifier genes. A study published in March from researchers in Singapore and Australia examined the genomes of almost 10,000 healthy people and looked for errors in more than 1,600 genes associated with severe pediatric disease. They found nine individuals ranging in age from 12 to 62 years old who showed no signs of illness despite having DNA profiles presumed to cause grave health issues in childhood. Last month, researchers presented new data at the European Human Genetics Conference in which they searched for 15 genetic conditions in about 900,000 individuals and found that, for some illnesses, the degree of severity is more variable than previously believed.

Separately, research has shown that 'carriers' of certain genetic diseases, who have just one affected gene, can have symptoms too. In these types of 'recessive' conditions, the people who show the classical manifestation of the disease have a pair of mutated genes. A person with just one nonworking version of a gene was supposed to be protected by the functioning second copy on the matching chromosome, but for a growing number of diseases, doctors and scientists now believe that being a carrier can come with health problems.

In October, researchers in Louisiana reported on a case involving a college football player who had heart palpitations during practice. The athlete was a carrier for the blood disorder sickle-cell disease—one of the most common genetic disorders in America. Up to 10 percent of Black Americans are carriers for sickle cell. The Louisiana man survived, but researchers noted that he had a dangerously irregular heartbeat during training and would need cardiac surgery.

Experts who study cystic fibrosis, which is caused by mutations in the CFTR gene, also want more attention on the health complications that carriers can experience. As many as one in 25 Americans of European descent is a carrier for cystic fibrosis. For this disease, reports of symptoms in carriers go back at least several decades, including infertility: in the mid-'90s, scientists found a handful of cystic-fibrosis carriers who lacked vas deferens, despite only one of their CFTR copies being mutated.