Syndromic and monogenic obesity in children from a population with frequent consanguinity: molecular spectrum and association with parental consanguinity
In a cohort of children with obesity from eastern Türkiye, a population characterized by frequent consanguinity, genetic testing revealed a 35.6% diagnostic yield dominated by autosomal recessive conditions like Bardet–Biedl syndrome, with parental consanguinity identified as the strongest predictor of a molecular finding.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Most cases of childhood obesity are complex, arising from a mix of many small genetic influences and the environment in which a child grows up. However, a smaller group of children carries a single, powerful genetic change that causes severe weight gain very early in life. Some of these children have a condition where the obesity is part of a larger pattern of health issues, affecting their development, eyes, or kidneys, while others have obesity as the primary feature. Understanding the specific genetic cause for these children is not just a matter of labeling; it can guide doctors on what other health problems to watch for and, in some cases, open the door to treatments that target the specific biological error. For families, a clear diagnosis can also provide answers about how the condition might be passed down to future children.
In a region of eastern Turkey where marriages between relatives are common, a team of researchers set out to uncover the specific genetic causes behind severe obesity in children. Because relatives share more of their DNA, children born to parents who are related are more likely to inherit two copies of a rare, faulty gene—one from each parent. This makes recessive genetic disorders, which require two copies to cause disease, more frequent in these populations. The researchers looked back at the medical records of 45 children from 41 families who had been referred to a specialized hospital for genetic testing. These children all had severe obesity, and many also showed other signs that suggested a genetic origin, such as the weight gain starting before age five, an intense and unquenchable hunger, delays in development, or unusual physical features.
The study found that a clear genetic cause could be identified in more than one-third of the children. The most common diagnosis was Bardet-Biedl syndrome, a condition where obesity is accompanied by issues like vision loss, extra fingers or toes, and kidney problems. Other identified causes included defects in the body's system for regulating appetite, a condition called Alström syndrome that affects the heart and eyes, and Prader-Willi syndrome, which involves severe hunger and developmental challenges. A striking feature of these findings was that the vast majority of the children with a diagnosis had inherited two identical copies of the faulty gene, a pattern that aligns with the high rate of marriages between relatives in the area. In fact, the researchers discovered that parental consanguinity was the single strongest clue pointing toward a genetic diagnosis; children with related parents were far more likely to have a molecular answer than those with unrelated parents.
The investigation also revealed that the genetic landscape in this population looked different from what is typically seen in other parts of the world. In many Western studies, the most common genetic cause of severe obesity is a single faulty copy of a gene called MC4R, which acts as a switch for appetite. Here, while that gene was involved, it was the recessive, two-copy version that caused the problem, and it was not the leading diagnosis. Instead, the team found that Bardet-Biedl syndrome was the most frequent culprit. The researchers also identified four genetic changes that had never been reported before, adding new pieces to the puzzle of how these conditions arise. They noted that some of the same genetic errors appeared in unrelated families, suggesting these specific changes might be more common in this region than previously known.
The implications of these findings extend beyond just counting cases. For the families involved, a diagnosis meant a shift in care. Children with syndromic obesity were placed on specific monitoring schedules for their eyes, kidneys, and hearts, conditions that can develop silently but have serious consequences. The study also highlighted that while certain symptoms like intense hunger or developmental delays were common in children with a genetic cause, they were not exclusive to them; many children without a genetic finding also had these symptoms. However, the history of parental relatedness stood out as a powerful, simple question that could help doctors decide which children are most likely to benefit from expensive and complex genetic testing. The researchers concluded that in populations where relatives marry, genetic testing should look broadly at many different genes, particularly those that cause recessive disorders, rather than focusing on just one or two common causes. This approach ensures that children with rare but treatable conditions are not missed.
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