Non-Syndromic Monogenic Obesity via the LEP Gene

The non-syndromic form of monogenic obesity is a group of single gene disorders with obesity as an isolated or predominant feature. Clinical features include severe early-onset obesity, hyperphagia, increased linear growth, delayed puberty, preserved reproductive function, hypocortisolemia and hyperinsulinemia (Albuquerque et al. 2015; Pigeyre et al. 2016).

The non-syndromic form of monogenic obesity was originally considered to be due to homozygous or compound heterozygous deleterious variants in causative genes, but heterozygous loss-of-function variants in these genes have been also widely reported to result in obesity, some of which can be incompletely penetrant (Albuquerque et al. 2015; Pigeyre et al. 2016). Known causative genes encode proteins in the leptin–melanocortin signaling pathway present in the hypothalamus with roles in regulation of food intake and energy expenditure.

The LEP gene (two coding exons) encodes leptin, which is secreted by white adipocytes and plays an important role in the regulation of body weight. So far, documented genetic defects of LEP for monogenic obesity include missense and truncating variants (Human Gene Mutation Database). Large deletions and duplications have not been reported in patients with monogenic obesity (Human Gene Mutation Database).

In a cohort of randomly selected 62 Pakistani children with early onset of severe obesity from consanguineous families, pathogenic LEP variants were found in 16.1% of the probands (Saeed et al. 2012). In another study, nine (36%) of 25 obese Pakistani children were found to have leptin deficiency and are homozygous for pathogenic LEP variants (Fatima et al. 2011).

Large deletions and duplications affecting the LEP gene have not been reported in patients with monogenic obesity (Human Gene Mutation Database).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the LEP gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.