Genetic tests reveal Bardet-Biedl syndrome in eye disease patients
Study findings support testing as foundation for BBS diagnosis, management
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A hand holds a glass tube containing a DNA molecule next to several identical tubes. (Photo by iStock)
Some people diagnosed with an inherited retinal disease (IRD), which affects the light-sensitive layer of the eye, may actually have unrecognized Bardet-Biedl syndrome (BBS), according to a study from Jordan involving 100 families with presumed isolated IRD.
After genetic testing identified disease-causing variants in genes associated with both BBS and IRD in 19 individuals from nine families, targeted medical evaluations uncovered previously overlooked features of the syndrome in most participants. As a result, 18 of the 19 participants met current diagnostic criteria for BBS.
The findings show that using genetic test results to guide additional medical evaluations “can detect patients with unrecognized BBS and facilitate appropriate clinical surveillance, genetic counseling, and management,” researchers wrote.
The study, “Clinical heterogeneity associated with Bardet–Biedl syndrome-related genes in presumed non-syndromic inherited retinal disease,” was published in Frontiers in Cell and Developmental Biology.
IRD is often one of the earliest signs of BBS
IRD comprises a group of genetic conditions that progressively damage the retina, the light-sensing tissue at the back of the eye, leading to worsening vision and, in some cases, blindness. While some IRDs affect only the eyes, others occur as part of broader genetic disorders that involve multiple organs, including BBS.
A rare disorder, BBS is caused by genetic mutations that impair tiny cellular structures called cilia. Because cilia help cells perform many vital processes, their disruption can lead to a wide range of symptoms. These can include vision loss due to IRD, obesity, learning disabilities, extra fingers or toes (polydactyly), kidney abnormalities, and urinary or reproductive system issues.
Traditionally, doctors make a diagnosis of BBS based on the presence of several of these characteristic features. However, many of these features develop gradually or vary considerably from one person to another, making the condition difficult to recognize early.
Because IRD is often one of the earliest signs of BBS, people whose other symptoms are mild or have not yet appeared may initially be diagnosed with what seems to be an isolated IRD rather than a disorder affecting multiple organs.
The European Reference Networks (ERNs) recently recommended incorporating genetic findings into the diagnostic process. Under these recommendations, a BBS diagnosis can be established in the presence of disease-causing variants in BBS-related genes alongside a selected set of clinical features, allowing doctors to recognize the disorder before all of its traditional signs have developed.
Evaluations uncover wide range of previously overlooked BBS features
In this study, a team of researchers in Jordan set out to better understand the clinical spectrum associated with mutations in BBS-related genes and determine whether some people with presumed isolated IRDs actually had BBS. They also compared how patients would be classified using the traditional clinical criteria for BBS versus the newer ERN recommendations.
By retrospectively analyzing data from 100 families with IRD, the researchers found that 19 people (11 men and eight women) from nine unrelated families carried disease-causing variants in five genes linked to both BBS and isolated IRD: CFAP418, BBS1, BBS2, BBS5, and CEP290.
The team then conducted comprehensive medical evaluations, including physical examinations and imaging tests, in these 19 patients to look for obvious or subtle signs of BBS outside the eyes that had been missed during the initial diagnosis.
Those evaluations uncovered a wide range of previously overlooked features of BBS. Obesity was the most common finding, affecting 16 participants (84.2%), followed by polydactyly and kidney abnormalities, each seen in seven participants (36.8%). Four participants had abnormalities affecting the urinary or reproductive system and four had intellectual disability (21.1% each).
[The findings] support adopting [genetic-driven] evaluation as the foundation for diagnosis and management of BBS-related diseases.
The findings substantially changed how many participants met the criteria for a BBS diagnosis. Using the traditional clinical criteria, 11 of the 19 participants qualified for a diagnosis. However, when the researchers applied the newer ERN recommendations, 18 of the 19 participants met the diagnostic criteria for BBS.
The detailed evaluations also highlighted the remarkable variability of the disorder, even among relatives carrying the same disease-causing variant. Eye disease varied widely in severity and type of retinal cell affected.
Features outside the eyes also varied considerably between and within families. Obesity was present in nearly all patients, but the presence and severity of other manifestations varied widely across patients. Some patients had obesity together with kidney disease, metabolic or hormonal abnormalities, developmental or behavioral features, and problems affecting the urinary or reproductive system.
“Collectively, these results demonstrated that the BBS-related features underlie a continuum of clinical manifestations rather than a [two-way] division between syndromic and isolated IRD,” the researchers wrote, adding that the findings “support adopting [genetic-driven] evaluation as the foundation for diagnosis and management of BBS-related diseases.”
The researchers also said the study expands the known clinical spectrum associated with CFAP418 mutations, which were the most common cause of BBS in this study, but have rarely been linked to the disease to date.
