Frequency of BBS and AS Gene Variants in a Cohort With Early-Onset Obesity

Background: Bardet-Biedl and Alström syndromes (BBS/AS) are rare, autosomal recessive diseases that often lead to early-onset obesity and hyperphagia. Both BBS and AS are diagnosed based on clinical features, which may include early-onset obesity, early-onset diabetes, cardiomyopathy, hyperphagia, visual impairment, polydactyly, renal anomalies, and cognitive impairment. More than 20 genes are associated with BBS/AS, but little is known about the frequency of variants in these genes in a population with early-onset, severe obesity, irrespective of clinical features. Methods: We sequenced 22 BBS genes and ALMS1 as part of the Uncovering Rare Obesity genetic testing program in 13,857 individuals with severe obesity (97th percentile BMI for age; >18 years old, BMI >40kg/m2). Variants were classified according to ACMG criteria as pathogenic/likely pathogenic (P/LP) or as variants of uncertain significance (VUS). Individuals were determined to be biallelic (>2 alleles in 1 gene), heterozygous (1 allele in only 1 gene), or composite heterozygous (1 allele per gene in multiple BBS genes). Results: In this cohort, 1.77% of individuals carried biallelic variants in BBS genes (1.13%) or ALMS1 (0.64%), including 0.33% with >2 P/LP alleles (BBS, 0.30%; ALMS1, 0.03%). It is unknown whether patients were sequenced because of suspected BBS/AS, and data are not available on related clinical characteristics, other than their severe early-onset obesity. Conclusions: In our cohort of >13,000 individuals with early-onset obesity, 1.8% were biallelic for variants in BBS genes or ALMS1. BBS/AS are heterogenous diseases that present with a variety of symptoms that evolve over time, and more research is needed to determine whether identification of individuals with biallelic variants may help identify patients in need of follow-up support regarding BBS/AS diagnosis. Today, these diseases are diagnosed based on clinical features, and genetic testing may help provide additional evidence to support a diagnosis.