Introduction Biallelic loss of function (LoF) mutations in the leptin receptor gene (LEPR) cause a striking phenotype of extreme early-onset severe obesity, hyperphagia and hypogonadotropic hypogonadism, growth hormone deficiency, and hypothyroidism. Currently, six Dutch patients (age 2-20 years), and 15 other patients (age <30 years) in Europe are described. Aim of this study was to estimate the number of LepR deficient patients in Europe.
Methods We developed a list of known LoF variants in LEPR from literature and in-house genetic data. We extracted allele frequencies for these variants from the Genome Aggregation Database (data of ~64.000 European individuals). Through a comprehensive epidemiologic analysis, we estimated the number of individuals with homozygous or compound heterozygous predicted LoF variants in LEPR in Europe analogous to Ayers et al. (JCEM 2018:2601-12) and a conservative estimation using only truncating and known LoF mutations.
Results By using only truncating and known LoF mutations, we make the conservative estimation of 710 (95% CI 377-1042) patients in Europe, suggesting that at utmost 3% of European patients with LepR deficiency are described in literature. By using the less conservative method of Ayers et al., the number of estimated European patients would be 8924 (95% CI 8115-9731).
Discussion We find a large gap between the estimated number of patients with LepR deficiency in Europe and those described in literature. This discrepancy suggests that the typical clinical phenotype of LepR deficiency (extreme weight gain in first years of life and often clinical signs of hypopituitarism) is not sufficiently recognized. A possible cause is lack of access to LEPR genetic testing, which only recently became accessible in Europe, or that the phenotype might not be overtly present or resolves over time. The young age of known patients suggests that high mortality could also play a role. With promising clinical trial results of MC4R-agonist treatment in LepR deficient patients, the importance of identifying these patients is paramount.