When Ludivine Verboogen and Romain Alderweireldt's third child was born in Belgium in late 2015, they marveled at his long fingers, dreaming of a future pianist. But soon, Ludivine grew worried: her son's muscles seemed weak, and thrice-weekly physiotherapy wasn't helping. “A lot of doctors were telling us that he was fine, nothing was wrong with him,” Romain recalled. Ludivine persisted, and shortly before his first birthday, they learned the devastating truth: their son had neonatal Marfan syndrome, a genetic connective tissue disorder that usually kills by 16 months. Romain lay down on his office floor, overwhelmed. His boss found him there and encouraged him to get back up and start working on a solution.
Romain and Ludivine soon discovered a paper describing 13 adults who, despite carrying multiple or dominant genetic mutations that normally cause grave childhood illness, were alive and healthy. These “genetic outliers” owe their luck to “modifier” genes that can mitigate or cancel out the effects of deadly mutations. Romain, a man on a mission, began combing genetic databases for people with Marfan mutations who lacked symptoms. He found 122 such individuals, including 24 with errors in the gene causing neonatal Marfan. Perhaps one of them held the key to a different life for his son.
The search for modifier genes isn't new. Catherine Boileau, a geneticist at INSERM, helped discover that mutations lowering activity of the PCSK9 gene could avert sky-high cholesterol, leading to a class of drugs. In sickle cell disease, a modifier gene suppresses fetal hemoglobin production; turning it off via gene-editing therapy (now FDA-approved) allows cells to make fetal hemoglobin as a backup. A study published in March from Singapore and Australia examined genomes of nearly 10,000 healthy people and found nine individuals aged 12 to 62 with DNA profiles presumed to cause severe pediatric disease - yet they showed no signs of illness. Last month, researchers presented data from about 900,000 individuals, finding that for some genetic conditions, severity is more variable than previously believed.
The original inspiration for Romain and Ludivine was the Resilience Project, led by scientists at the Icahn School of Medicine at Mount Sinai. Paused for years, the project is now being rebooted with AI tools to scan over 2 million genomes for more than 500 rare diseases, aiming to identify modifier genes and develop drugs that mimic their effects. In a paper published last week, scientists note that modifier genes have been found in around 100 different human diseases.
The mystery of why some people with deadly gene variants escape symptoms traces back a century to fruit fly studies, where expected mutations sometimes caused only partial changes. Scientists now know that environmental factors - like diet for phenylketonuria - and epigenetic markers can influence symptom severity. Caroline Wright, a geneticist at the University of Exeter, notes that large population studies have revealed that symptoms caused by pathogenic mutations are often milder than doctors believed, partly because early genetic studies focused on sick individuals, biasing perceptions of harm.
Dusan Bogunovic, director of the Center for Genetic Errors of Immunity at Columbia University, published a paper in March highlighting another factor: gene skewing, where one parent's copy of a gene is four times as active as the other. If the healthy copy is more active, symptoms may be far fewer. This skewing might even influence Marfan syndrome outcomes: a study of 80 people with Marfan and 80 healthy volunteers found a roughly fourfold difference in fibrillin-1 gene activity in both groups, suggesting skewing contributes to symptom variability.
Romain and Ludivine's son has not yet needed heart surgery, but they are still eager to identify outliers. They started the 101 Genomes Foundation to amass whole-genome data from people with Marfan mutations; in the past decade, they've collected over 230 genomes. At the European Conference on Rare Diseases in June, their team presented five potential modifier genes. In as-yet-unpublished data, they've identified a variant of an additional modifier gene that affects the heart's ability to contract and has a strong protective effect against Marfan mutations, according to Bart Loeys, a clinical geneticist at the University of Antwerp. “If nature has the means of correcting or buffering the effects of a pathogenic variant in one gene, we can learn from that,” he said. “Maybe we can try to mimic that in other patients.”