CLINICAL RESEARCH www.jasn.org Risk Factors for Severe Renal Disease in Bardet–Biedl Syndrome † † ‡ † Elizabeth Forsythe,* Kathryn Sparks, Sunayna Best,* Sarah Borrows, Bethan Hoskins, | †† Ataf Sabir,§ Timothy Barrett, Denise Williams,¶ Shehla Mohammed,** David Goldsmith, ‡‡ ‡ † David V. Milford,§ Detlef Bockenhauer, Lukas Foggensteiner, and Philip L. Beales* *Genetics and Genomic Medicine Program, University College London Great Ormond Street Institute of Child Health, †National Bardet–Biedl Syndrome Service, Department of Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom; ‡‡University College Hospital Center for Nephrology, Great Ormond Street Hospital, London, United Kingdom; ‡Nephrology Unit, Queen Elizabeth II Hospital, Birmingham, United Kingdom; §Nephrology Unit and |Department of Endocrinology, Birmingham Children’s Hospital, Birmingham, United Kingdom; ¶Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham, United Kingdom; and **Clinical Genetics Unit and ††Nephrology Unit, Guy’s Hospital, London, United Kingdom 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 (BBS1–19)havebeenidentified, of which mutations in BBS1 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 syn- drome 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 BBS10,mutationsinBBS1 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. J Am Soc Nephrol 28: 963–970, 2017. doi: 10.1681/ASN.2015091029 Bardet–Biedl syndrome (BBS) is a rare autosomal inter- and intrafamilial phenotypic variation is recessive ciliopathy characterized by rod-cone dys- observed.2 trophy, renal malformations, learning difficulties, Structural renal and urinary tract anomalies obesity, postaxial polydactyly, and hypogonad- and renal dysfunction is a cause of considerable ism.1 Nineteen disease-causing genes have been identified (BBS1–BBS19) in the last two decades. BBSgenescode for proteins that localize to the cilia Received September 16, 2015. Accepted August 7, 2016. or the basal body and are thought to be involved in Published online ahead of print. Publication date available at cilia development and maintenance.2 Mutations in www.jasn.org. BBS genes lead to defective cilia. Sequencing of Correspondence: Dr. Elizabeth Forsythe, Genetics and Genomic known disease-causing genes confirms a clinical Medicine Programme, Institute of Child Health, 30 Guilford Street, diagnosis of BBS in around 80% of patients.2 Vari- London, WC1N 1EH, UK. Email: [email protected] able expressivity is a hallmark of BBS and both Copyright © 2017 by the American Society of Nephrology J Am Soc Nephrol 28: 963–970, 2017 ISSN : 1046-6673/2803-963 963 CLINICAL RESEARCH www.jasn.org morbidity and reported to affect 53%–82% of patients with Diagnosis was on the basis of clinical phenotyping. All BBS.2–6 The primary renal phenotype is highly variable, rang- patients underwent genetic testing. On sequencing 13 disease- ing from cystic tubular disease, dysplastic renal disease, and related genes, molecular confirmation of the diagnosis was FSGS to concentrating defects.3–7 Lower urinary tract dys- achieved in 80% of all pedigrees (216 of 270) and in 77% of all function is observed in many patients and may have upper patients (265 of 350). A full list of genotypes can be found in renal tract sequelae.8 It is thought that ciliary dysfunction Supplemental Table 1. The sex distribution was 54% male and leads to disturbance of the noncanonical Wnt-signaling path- 46% female. Sixty-nine percent of patients were white, 28% way which may contribute to the development of cystic kidney were Southeast Asian, and the remaining 3% had a mixture of disease classically associated with BBS.2 Secondary renal dis- other backgrounds (black, Chinese, and Ashkenazi Jewish). ease may occur as a consequence of hypertension and diabetes, The distribution of genotypes is demonstrated in Figure 1. both of which are frequently observed in this population. For the purpose of statistical analysis, mutation type was clas- The high frequency of renal disease in BBS is a cause of great sified according to severity. One hundred twenty-five patients anxiety among patients because of the devastating effect this had two missense mutations, 82 had two truncating mutations can have on quality of life, morbidity, and mortality.4–6 This (nonsense, frameshift, splice site, or a combination), 39 had a study examines renal disease in the largest reported cohort of combination of missense and truncating mutations, and the patients with BBS and identifies indicators of disease that remaining 19 patients had other mutation combinations, in- are directly relevant to patient management and clinical cluding exon deletions and start-codon aberrations. stratification. Age of Onset of Renal Disease One hundred fifty-six pediatric patients were seen in the RESULTS pediatric clinics. Of these, we were able to retrospectively obtain the earliest recorded age of onset of stage9 2–5 CKD Overview of the BBS Population (CKD2–5) in 49 pediatric patients attending the BBS clinic Three hundred fifty patients attended the adult and pediatric (Figure 2). All pediatric patients with CKD4–5werediagnosed national BBS clinics in Birmingham and London over a 4-year before the age of 5 years. The majority of patients with any period (2010–2014). The patient population ranged in age stage of CKD presented before the age of 10 years. Because the from birth to 60 years old, with a peak frequency in the 6–10 peak referral age to the clinic is late childhood, a later-recorded years-of-age category, and with few older adults. onset of CKD is likely to reflect significant ascertainment bias Figure 1. The BBS1 genotype predominates in the UK population of patients with Bardet-Biedl syndrome followed by mutations in BBS10 and BBS2. Distribution of genotypes. 964 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 963–970, 2017 www.jasn.org CLINICAL RESEARCH Ninety percent of children and 96% of adults were able to comply. Urinalysis was normal in all those considered free of renal disease. Table 1 demonstrates the number of patients seen in the adult and pediatric clinics and the prevalence of CKD indicators. Table 2 demonstrates the prevalence of CKD2–5 in the adult and pediatric populations presenting to the BBS clinics. The age at which patients reached CKD5 is known for 20 patients in this cohort. Of these patients, 70% (n=14) had reached CKD5 by the age of 20 years. The age of onset of CKD5 was delineated retrospectively and Kaplan–Meier sur- vival to CKD5 is demonstrated in Figure 4. Figure 2. CKD4-5 was predominantly diagnosed within the first Genotype and mutation-type analyses in adults with BBS year of life in pediatric patients with BBS. Age at which renal revealed statistically significant correlations with the presence disease (CKD2–5) was first noted in pediatric patients with BBS of severe renal disease defined as CKD3b–5(eGFR,45 ml/min (n=49). per 1.73 m2). Univariable logistical regression analysis indi- cated that mutations in BBS2, BBS10,andBBS12 were more as patients may have asymptomatic renal disease and no pre- likely to be associated with severe renal disease than mutations vious renal sonography. in BBS1 (P values of 0.02, ,0.001, and 0.03, respectively) Observations from the national BBS clinics suggest that (Table 3). Univariable logistical regression analysis of muta- patients either develop CKD4–5 in childhood or maintain tion type revealed that truncating mutations and truncating/ normal or near-normal renal function into adulthood. Figure missense mutations were statistically associated with severe 3 demonstrates that the frequency of CKD4–5 remains similar renal disease in comparison to two missense mutations in adults and children (8% and 6% respectively). (P values of ,0.001 and 0.01, respectively) (Table 3). Proportional frequencies of stage 2, 3,4, and 5CKDin adults Prevalence of CKD were compared for the commonest genotypes, BBS1 and eGFR results were available for 189 adults and 133 pediatric BBS10, as outlined in Figure 5. Patients with BBS1 mutations patients. Seventy percent of adult patients had at least two are more likely to be disease-free or have early stage CKD. eGFR readings. The prevalence