GNB1 and obesity: Evidence for a correlation between haploinsufficiency and syndromic obesity

Lotte Kleinendorst, Ozair Abawi, Niels Vos, Eline S. van der Valk, Saskia M. Maas, Angela T. Morgan, Michael S. Hildebrand, Jorge D. da Silva, Ralph J. Florijn, Peter Lauffer, Jenny A. Visser, Elisabeth F. C. van Rossum, Erica L. T. van den Akker, Mieke M. van Haelst

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Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader–Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.
Original languageEnglish
JournalClinical obesity
Early online date2024
Publication statusE-pub ahead of print - 2024


  • Prader–Willi like
  • genetic obesity
  • leptin-melanocortin pathway
  • obesity syndrome
  • syndromal obesity

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