A new study co-authored by LAU’s human genetics team has underscored the importance of confirming how genetic changes affect the body and monitoring people over time before drawing firm conclusions about disease risk.

The research highlights the need to refine how genetic variants are classified and provide more accurate genetic counseling, especially when predictions about a variant do not match the medical evidence. They also show why a variant classified as disease-causing should be reevaluated rather than treated as definitive proof that disease will develop.

What may first seem like a minor finding has already influenced clinical decisions in five pregnancy cases.

The study involved faculty from the Department of Human Genetics at the Gilbert and Rose-Marie Chagoury School of Medicine: Dr. Eliane Chouery, professor and genetics discipline co-coordinator; Dr. André Megarbane, assistant dean for research and department chair; and Dr. Cybel Mehawej, associate professor and genetics discipline co-coordinator.

Published in the Journal of Neuromuscular Diseases, “Recurrent nonsense p.Trp3416* variant in the DMD gene identified in healthy Lebanese individuals: Implications for variant classification and genotype-phenotype correlations” examined five unrelated Lebanese families referred for advice about inherited conditions or genetic testing before marriage. The researchers read the protein-making parts of their DNA, then confirmed the finding with a second, more focused test. The same change, known as p.Trp3416*, appeared in each family.

p.Trp3416* causes the body to stop producing dystrophin, a critical muscle protein,  prematurely. This could lead to Duchenne muscular dystrophy, namely increased muscle weakness, as well as related muscle and heart conditions.

Classic Duchenne muscular dystrophy usually becomes apparent in early childhood, commonly between ages two and five, but “we would avoid stating that DMD can be ruled out based on age alone,” said Dr. Mehawej. She distinguished classic Duchenne disease from the broader range of dystrophin-related disorders, which include Becker muscular dystrophy, milder forms of disease, and conditions affecting only the heart.

However, the three men, aged 35, 65 and 67, showed no signs of a dystrophin-related muscle or heart disorder. Physical examinations, heart electrical recordings, heart ultrasound scans and blood tests for muscle damage were all normal. The two older men’s good health was especially relevant to understanding whether p.Trp3416*  necessarily causes serious disease.

Their ages made the normal exam results particularly reassuring, said Dr. Chouery, adding that the likelihood of “developing a clinically significant DMD-related disorder later in life was extremely low.”

Yet computational tools predicted that the change would be harmful, and several genetic databases classified it as disease-causing or likely disease-causing.

ClinVar, a database that links genetic variants with health information, contained conflicting assessments of the change. The variant also appeared to be extremely rare in the general population. In gnomAD, one of the world’s largest genetic databases, it appeared only six times among more than a million copies of the gene.

Together, these findings highlighted the difficulties of interpreting rare genetic changes. Despite predictions and database classifications suggesting that p.Trp3416* could cause disease, the three men carrying it showed no signs of a dystrophin-related disorder.

The researchers could not determine how or why the men remained healthy. Differences in the DNA surrounding the change suggested that the families probably did not inherit it from a recent common ancestor, but possibly from a more distant shared origin.

The team also considered several biological explanations: the change may still allow the body to produce some functional dystrophin, or other genes and biological processes may help protect against its effects. None of these possibilities was confirmed, warranting further studies to determine the biological consequences of the genetic change and whether it can be considered harmless in all carriers.

The findings have already influenced clinical decisions, enabling the team “to prevent approximately five fetuses from being unnecessarily terminated” after the results were considered in the appropriate clinical context, said Dr. Chouery. She emphasized that sharing such observations with the wider scientific and medical community can have substantial consequences for clinicians, genetic counselors, patients and families.

“Genetic testing is extremely powerful, but a genetic result should never be interpreted in isolation,” said Dr. Megarbane. A disease-causing classification in a database does not necessarily establish a clinical diagnosis, he explained, especially when a person’s health and the family’s inheritance pattern do not match the expected disease.

“This is why a thorough clinical evaluation, combined with an extensive review of the literature and, importantly, the experience and clinical judgment of geneticists, is essential,” he added.

Based on their findings, the researchers recommend that families discuss both the genetic result and the medical evidence with a clinician who can explain inherited health risks. Continued health checks can identify problems if they emerge, while further research may clarify the risk over time.

Explaining what is known and what remains uncertain can help people make better-informed decisions about having children and arranging follow-up care without treating a computer prediction as final.

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