ESPE Yearbook of Paediatric Endocrinology

robertkj@uwm.edu International Journal of Obesity 2022 May 13:1–9. doi: 10.1038/s41366-022-01139-7. https://pubmed.ncbi.nlm.nih.gov/35562395/

Brief Summary: This exploratory study presents the findings and experiences from n=117 children with obesity (BMI ≧97^th percentile for age and sex) participating in a pediatric weight management program over an 18-month period in which targeted DNA sequencing was performed for 40 genes known to cause rare genetic disorders of obesity. No homozygous or compound heterozygous variants were identified, but 72 patients (61.5%) had at least one heterozygous variant among the analyzed genes, of which 22 patients (18.8%) had 2–4 variants.

Testing for rare genetic diseases of obesity is recommended in children with early-onset obesity (%BMI_P95 ≥120% before 5 years of age) that have clinical features of genetic obesity syndromes (including hyperphagia) and/or a family history of severe obesity [1]. Most variants identified in this cohort were rare (<0.05% minor allele frequency in gnomAD) [2] and of uncertain significance according to the ACMG guidelines [3] (4 patients had variants classified as “likely pathogenic/pathogenic” in autosomal recessive inherited genes, 8 patients a PCSK1 variant classified as “risk” factor, 1 patient a MC4R variant classified as “likely pathogenic” in addition to the PCSK1 “risk” variant). In contrast, previous studies on genetic obesity disorders reported an underlying causative genetic defect in 2–13% of pediatric patients with severe obesity, excluding variants of uncertain significance [4,5].

This study clearly shows the current challenge of dealing with findings of genetic tests that identify variants of uncertain significance and highlights the need to develop clinical tools to increase provider confidence in offering genetic testing and communicating genetic results with families. Further research in larger cohorts, which includes detailed phenotypic characterization of the patients, segregation and functional analysis is needed to understand how variants of uncertain significance or multiple variants influence obesity and hyperphagia.

References: 1. Styne, D.M., et al., Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2017. 102(3): p. 709–757. 2. gnomAD Genome Aggregaion Database. 3. Richards, S., et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 2015. 17(5): p. 405–24. 4. Hendricks, A.E., et al., Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity. Sci Rep, 2017. 7(1): p. 4394.5. Kleinendorst, L., et al., Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center. PLoS One, 2020. 15(5): p. e0232990.