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Updated: Jul 9, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

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High-frequency variants in PKA signaling-related genes within a large pediatric cohort with obesity or metabolic

Michelle Bloyd1, Ninet Sinaii2, Fabio Rueda Faucz1

  • 1Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD, United States.

Frontiers in Endocrinology
|November 29, 2023
PubMed

Insights

This study identified new genetic variants linked to obesity in diverse youth by examining the cAMP-dependent protein kinase (PKA) signaling pathway. Findings advance understanding of heritable obesity and personalized treatment strategies.

Area of Science:

  • Genetics
  • Metabolic Disorders
  • Pediatrics

Background:

  • Pediatric obesity rates are rising globally, particularly in non-European populations.
  • Genome-wide association studies (GWAS) have identified obesity-associated loci, but research in diverse children is limited.
  • Understanding genetic variants in pathways like cAMP-dependent protein kinase (PKA) is crucial for personalized obesity therapies.

Purpose of the Study:

  • To identify genetic variants associated with obesity in a diverse pediatric cohort.
  • To investigate the role of the PKA signaling pathway in childhood obesity.
  • To uncover novel genetic associations for targeted therapeutic development.

Main Methods:

  • Targeted exome sequencing of 53 PKA signaling-related genes.
  • Analysis of genomic DNA from a large, ethnically diverse cohort of obese or metabolically challenged youth.
  • Confirmation of high-frequency variants and identification of novel gene variants.

Main Results:

  • 49 high-frequency genetic variants were confirmed within the PKA pathway genes.
  • A novel variant in the PDE11A gene (c.152C>T) was identified.
  • Several variants showed associations with metabolic characteristics specific to ethnic groups.

Conclusions:

  • Targeted sequencing of PKA pathway genes successfully identified novel genetic associations with obesity in a diverse population.
  • These findings contribute to a better understanding of the genetic underpinnings of childhood obesity.
  • The study highlights the potential for PKA pathway variants in developing personalized obesity treatments.
Abstract

Keywords:
GPCRsT2DMgeneticsliver diseaseobesitypediatricprotein kinase Atargeted exome sequencing

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