Risk Factors for Severe Renal Disease in Bardet–Biedl Syndrome

Abstract

Bardet-Biedl syndrome is a rare autosomal recessive, multisystem disease characterized by retinal dystrophy, renal malformation, obesity, intellectual disability, polydactyly, and hypogonadism. Nineteen disease-causing genes () have been identified, of which mutations in are most common in North America and Europe. A hallmark of the disease, renal malformation is heterogeneous and is a cause of morbidity and mortality through the development of CKD. We studied the prevalence and severity of CKD in 350 patients with Bardet-Biedl syndrome-related renal disease attending the United Kingdom national Bardet-Biedl syndrome clinics to further elucidate the phenotype and identify risk indicators of CKD. Overall, 31% of children and 42% of adults had CKD; 6% of children and 8% of adults had stage 4-5 CKD. In children, renal disease was often detected within the first year of life. Analysis of the most commonly mutated disease-associated genes revealed that, compared with two truncating mutations, two missense mutations associated with less severe CKD in adults. Moreover, compared with mutations in, mutations in associated with less severe CKD or lack of CKD in adults. Finally, 51% of patients with available ultrasounds had structural renal abnormalities, and 35% of adults were hypertensive. The presence of structural abnormalities or antihypertensive medication also correlated statistically with stage 3b-5 CKD. This study describes the largest reported cohort of patients with renal disease in Bardet-Biedl syndrome and identifies risk factors to be considered in genetic counseling.

Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome

“…In the recent publication on the English cohort, it has been demonstrated that mutations in BBS2, 10 and 12 correlated with a most severe renal dysfunction compared with BBS1 , confirming previous findings [4]. In addition, the study pointed that truncating mutations compared with missense mutations were associated with kidney dysfunction, suggesting that any BBS gene when strongly affected may lead to kidney disease.…”

“…The majority of reports show that more than half of the BBS patients exhibit normal eGFR [11, 12]. A recent retrospective study on a total of 350 BBS patients from the United Kingdom showed that the prevalence of CKD stage II-V were 42% and 31% in adult and children respectively and no difference between genders have been reported [4]. Patients with normal glomerular filtration rate (GFR) included either subjects with structural renal abnormalities and individuals with no any significant anomalies on kidney ultrasound.…”

“…It is still unclear whether the nature of the genetic mutation may affect the severity of the phenotype. Possibly, truncating mutations rather than missense mutations may lead to milder phenotype [4]. Another possibility is the oligogenic feature of the BBS, where different genes may influence the severity of the phenotype.…”

The Kidney in Bardet-Biedl Syndrome: Possible Pathogenesis of Urine Concentrating Defect

“…Some reports showed that BBS1 mutations are associated with a less severe phenotype compared with other BBS genes [19] , especially BBS10 [20,21] . However, in a recent study, it was demonstrated that biallelic truncating mutations in any gene correlated with more severe renal disease compared with missense mutations, suggesting that any BBS gene, when strongly affected, may result in severe kidney dysfunction [21] .…”

Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome

“…The syndrome has a genetic origin, and to date 21 genes have been associated with human BBS but it is presumable that other unknown genes are yet to be discovered [1]. Even though many efforts have been devoted to address genotype-phenotype correlation, there is still little information on this issue [2-4]. …”