Monogenic obesity

Monogenic obesity can result from pathogenic variants in a growing number of genes and encompasses both non-syndromic and syndromic forms. The considerable phenotypic overlap observed between these conditions suggests a continuum of clinical presentations rather than strictly distinct entities. Several genes, including MC4R, LEPR, LEP, POMC and PCSK1, are typically associated with severe early-onset obesity in which hyperphagia and adiposity are the predominant clinical manifestations. Variants in genes such as SIM1, SH2B1 and NTRK2 further illustrate the overlap between non-syndromic and syndromic obesity, as affected individuals may present with obesity as a leading feature but may also exhibit variable neurodevelopmental, behavioural or cognitive abnormalities. Similar phenotypic overlap has been observed across a broader range of obesity-associated genes, further underscoring the heterogeneous nature of genetic obesity.

The genetic conditions associated with monogenic obesity follow heterogeneous inheritance patterns. Autosomal dominant and autosomal recessive forms both occur in the non-syndromic as well as in the syndromic spectrum. Syndromic forms additionally include imprinting and other chromosomal mechanisms.

• Where severe early-onset obesity is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity supports condition-specific monitoring and management decisions; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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