Protein-truncating variants in APBA1 in minors with severe, early-onset obesity: implications for genetic testing

Abstract Background Severe, early-onset obesity is a monogenic disorder in a subset of patients. Recently, rare protein-truncating variants (PTVs) in BSN and APBA1 have been implicated as monogenic causes of obesity. Truncating variants in these two genes have been associated with adult-onset monogenic obesity. Here, we aimed to investigate the occurrence of rare PTVs in APBA1 and BSN in minors with severe obesity manifesting in early childhood or adolescence. Methods Previously obtained exome data of 209 children and adolescents (0–18 years) with severe obesity manifesting in early childhood or adolescence genetically tested at the Ulm University Medical Center between April 2022 and May 2024 were mined for rare PTVs in APBA1 (NM_ 001163.4; NP_ NP_001154.2) and BSN (NM_003458.4; NP_003449.2). In all patients, monoallelic, and in the case of autosomal-recessive inheritance, biallelic likely pathogenic and pathogenic variants in well-known obesity-associated genes were excluded. Clinical re-evaluation was performed in two identified cases with rare potentially protein-truncating variants in APBA1. Results The first patient (male, 15 years) presented with a BMI of 33.7 kg/m2 (BMI z-score: 2.7) after nine years of excessive weight gain despite life-style interventions. He had a body fat percentage of 49.5% and showed hyperphagia. The patient displayed impaired expressive language development, dyslexia and an IQ of 84. His mother also had obesity and dyslexia while his father and younger sister were unaffected. We identified the heterozygous, likely pathogenic variant APBA1:c.814C > T;p.(Gln272*) in the index patient and his mother. The second patient (male, 6 years) presented with a BMI of 30.0 kg/m2 (BMI z-score: 3.8), a body fat percentage of 43.6% and hyperphagia. The child had upslanting palpebral fissures and showed impaired expressive language development. Both parents of the boy were affected by severe obesity and underwent bariatric surgery. We identified the heterozygous variant of unknown significance APBA1:c.2442 + 3A > C predicted to impair proper splicing in the index patient and his mother. Conclusion We conclude that rare potentially protein-truncating variants in APBA1 are also found in some minors with early-onset and severe obesity. Therefore, those variants might not be restricted to adult-onset disease. We therefore propose to include APBA1 in diagnostic genetic testing for monogenic obesity in minors and adults.