Non-Syndromic Monogenic Obesity via the PCSK1 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 PCSK1 gene (14 coding exons) encodes pro-protein convertase subtilisin/kexin type 1, which acts in the pathway of post-translational processing of prohormones and neuropeptides. So far, documented genetic defects of PCSK1 include missense, splicing, nonsense, small deletion/insertions and large deletions (Human Gene Mutation Database).

In a study of 845 non-consanguineous extremely obese European subjects, eight heterozygous PCSK1 rare nonsynonymous variants were found in eight unrelated individuals (0.95%), which probably explained obesity attributed to partial prohormone convertase 1 deficiency (Creemers et al. 2012).

Large deletions have been reported involving the PCSK1 gene, but are relatively uncommon (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 PCSK1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.