LEPR Deficiency: Prevalence and Importance of a Novel Mutation and Significant Genetic Variants, Usually Underestimated

ABSTRACT

Objective: Diagnostic testing for leptin receptor deficiency, a rare cause of obesity, should be performed in cases where it may affect the clinical management. Therefore, molecular tests are required to grant a conclusive diagnosis. In this study, the clinical utility of molecular testing and the importance of genetic counselling resulting from all the genetic variants, including both, disease-causing mutations and polymorphisms has been outlined.

Material and Methods: The study consisted of samples of leukocyte-DNA in sixteen clinically deficient patients of leptin receptor. In order to identify the molecular basis, the LEPR gene sequencing was employed using next-generation sequencing platform(MiSeq System, Illumina) for all the exons, introns and exon-intron binding regions. In-silico analyses for novel mutations were carried out using SIFT, Polyphen2 and Mutation Taster. Paternal carrier testing was also accomplished.

Results: The causative mutation was identified in three out of sixteen patients with leptin receptor deficiency (18.75%). All these three patients carried the same, novel, homozygous p.P639L (c.1916C>T) mutation. Most interestingly, 62.5% of the patients (n=10) were found to be carrying at least one of the possible disease-risk-polymorphisms related to obesity, increased body mass index, insulin resistance and glucose intolerance.

Conclusion: This study presented with two important outcomes. First, the novel p.P639L mutation could be identified in three different patients and, second, but most important, the fact that polymorphisms of the leptin receptor gene, usually underestimated, is the main genetic predisposition factor for the Turkish population. It is, therefore, critical to identify not only the mutations but all the genetic variants responsible for leptin receptor deficiency, to aid in diagnosis, prevention, prognosis, treatment, and research.