Kidney failure in Bardet-Biedl syndrome

Jennifer R Meyer, Anthony D Krentz, Richard L Berg, Jesse G Richardson, Jeremy Pomeroy, Scott J Hebbring, Robert M Haws, Jennifer R Meyer, Anthony D Krentz, Richard L Berg, Jesse G Richardson, Jeremy Pomeroy, Scott J Hebbring, Robert M Haws

Abstract

The aim of this study was to explore kidney failure (KF) in Bardet-Biedl syndrome (BBS), focusing on high-risk gene variants, demographics, and morbidity. We employed the Clinical Registry Investigating BBS (CRIBBS) to identify 44 (7.2%) individuals with KF out of 607 subjects. Molecularly confirmed BBS was identified in 37 KF subjects and 364 CRIBBS registrants. KF was concomitant with recessive causal variants in 12 genes, with BBS10 the most predominant causal gene (26.6%), while disease penetrance was highest in SDCCAG8 (100%). Two truncating variants were present in 67.6% of KF cases. KF incidence was increased in genes not belonging to the BBSome or chaperonin-like genes (p < 0.001), including TTC21B, a new candidate BBS gene. Median age of KF was 12.5 years, with the vast majority of KF occurring by 30 years (86.3%). Females were disproportionately affected (77.3%). Diverse uropathies were identified, but were not more common in the KF group (p = 0.672). Kidney failure was evident in 11 of 15 (73.3%) deaths outside infancy. We conclude that KF poses a significant risk for premature morbidity in BBS. Risk factors for KF include female sex, truncating variants, and genes other than BBSome/chaperonin-like genes highlighting the value of comprehensive genetic investigation.

Trial registration: ClinicalTrials.gov NCT03013543 NCT03651765.

Keywords: Bardet-Biedl syndrome; chronic kidney disease; ciliopathies; genetic association studies; urogenital abnormalities.

Conflict of interest statement

RH is a consultant for Rhythm Pharmaceuticals and Axovia Therapeutics, LLC and principal investigator for the Setmelanotide Phase 2 Treatment Trial in Patients with Rare Genetic Obesity (ClinicalTrials.gov NCT03013543) and Long Term Extension Trial of Setmelanotide (Clinical Trials.gov NCT03651765) sponsored by Rhythm Pharmaceuticals. JP receives research funding from Rhythm Pharmaceuticals and Axovia Therapeutics. SH received research funding from Rhythm Pharmaceuticals. All other authors report no conflict of interest.

© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
(A) Kidney failure (KF) prevalence by age and sex; (B) All‐cause mortality risk in KF population
FIGURE 2
FIGURE 2
Gene frequency in kidney failure (KF) cohort compared with all CRIBBS participants [Colour figure can be viewed at wileyonlinelibrary.com]
FIGURE 3
FIGURE 3
Distribution of CRIBBS participants with molecular diagnosis by (A) gene variant and (B) gene group [Colour figure can be viewed at wileyonlinelibrary.com]
FIGURE 4
FIGURE 4
Kidney failure (KF) incidence by age and protein group

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