EP274: Frequency of Bardet-Biedl syndrome and Alström syndrome gene variants in a cohort with early-onset obesity

Abstract

Bardet-Biedl syndrome (BBS) and Alström syndrome are rare, autosomal recessive ciliopathies that often lead to early-onset obesity and hyperphagia. Both BBS and Alström syndrome are diagnosed based on presentation of clinical features that 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 and Alström syndrome, but little is currently known about the frequency of variants in these genes in a population with severe, early-onset obesity, irrespective of clinical features. We sequenced 22 BBS genes and ALMS1 as part of the Uncovering Rare Obesity diagnostic genetic testing program in 8459 individuals with severe (Class III) obesity (<18 years old, >/=97th percentile body mass index (BMI) for age; >/=18 years old, BMI >/=40kg/m2). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria as pathogenic/likely pathogenic (P/LP) or as a variant of uncertain significance (VUS). Individuals were determined to be biallelic (2 or more alleles in 1 gene), heterozygous (1 allele in only 1 gene), or composite heterozygous (1 allele per gene in multiple BBS genes). In this cohort, 1.96% of individuals carried biallelic variants in BBS (1.36%) or ALMS1 (0.60%) genes, including 0.34% with >/=2 P/LP alleles (BBS 0.30%, ALMS1 0.04%); this frequency was 0.24% after excluding patients from a known BBS specialty clinic. In addition, 1.62% were biallelic with >/=1 VUS alleles, 26.8% carried a single heterozygous variant in only 1 gene, and 4.0% carried variants in more than one BBS gene. It is unknown whether patients were sequenced due to suspected BBS or Alström syndrome, and data is not available on related clinical characteristics, other than their severe early-onset obesity. In our cohort of 8459 individuals with early-onset obesity, 1.96% of individuals were biallelic for variants in genes associated with BBS or Alström syndrome. BBS and Alström syndrome 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 and Alström syndrome diagnosis. Today, these diseases are diagnosed based on clinical features, and genetic testing may help provide additional evidence to support a diagnosis.