Maternal transmission bias of inherited genetic variants in severe early-onset obesity

Abstract Background: Obesity is highly influenced by genetics, with stronger genetic component in severe early-onset obesity (EOO). Heterozygous rare sequence variants (RSVs) affecting genes of the leptin-melanocortin pathway and hypothalamic function cause EOO, with variable expressivity and incomplete penetrance. We aimed to define whether and how parental inheritance could influence expressivity and penetrance. Methods: Observational study, systematic review and meta-analysis of reported inherited likely pathogenic heterozygous RSVs associated to non-syndromic EOO in 17 candidate genes was performed. Parental phenotype and proband’s birthweight were obtained when available. Child-feeding practices in transmitting and non-transmitting mothers were compared in a subsample using a validated questionnaire. Results: We identified 38 studies reporting 216 children with EEO and inherited heterozygous RSVs in candidate genes. A significant maternal over-transmission was observed (61.6%, 1.66:1, p = 0.0004), higher for RSVs inherited from severely obese parents (84%, 5.2:1, p = 0.0005). Patients with maternally inherited RSVs had an increased birthweight compared with patients with non-maternally inherited RSVs. Transmitting mothers manifest lower perceived responsibility for child feeding behavior when compared to non-transmitting mothers of either obese or non-obese children. Conclusions: A maternal over-transmission bias of inherited dominant RSVs disrupting genes of the leptin-melanocortin pathway contributes to severe EOO. Thus, synergistic effects of RSVs present in both, transmitting mothers and their children, can explain the more severe phenotype in the children. Prenatal factors during gestation and postnatal deregulation of eating behavior due to maternal carelessness may contribute to this bias. Identification of this risk factor may be useful for early intervention to prevent long term consequences of severe EOO.