AUTHOR=Loid Petra , Pekkinen Minna , Reyes Monica , Mustila Taina , Viljakainen Heli , Jüppner Harald , Mäkitie Outi 

TITLE=GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children

JOURNAL=Frontiers in Pediatrics

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2020.00145

DOI=10.3389/fped.2020.00145

ISSN=2296-2360

ABSTRACT=<p><bold>Context:</bold> Pseudohypoparathyroidism type Ia (PHP1A) is caused by inactivating mutations involving <italic>GNAS</italic> exons 1–13, encoding the alpha-subunit of the stimulatory G protein (Gsα). Particularly PHP1A, but also other disorders involving the Gsα-cAMP-signaling pathway, have been associated with early-onset obesity. Thus, patients with mutations in the genes encoding PDE4D and PRKAR1A can also be obese. Furthermore, epigenetic <italic>GNAS</italic> changes, as in pseudohypoparathyroidism type Ib (PHP1B), can lead to excessive weight.</p><p><bold>Objective:</bold> Search for genetic variants in <italic>GNAS, PDE4D</italic>, and <italic>PRKAR1A</italic> and for methylation alterations at the <italic>GNAS</italic> locus in Finnish subjects with isolated severe obesity before age 10 years.</p><p><bold>Methods:</bold> Next generation sequencing to identify pathogenic variants in the coding exons of <italic>GNAS, PDE4D</italic>, and <italic>PRKAR1A</italic>; Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-sensitive MLPA (MS-MLPA) to search for deletions in <italic>GNAS</italic> and <italic>STX16</italic>, and for epigenetic changes at the four differentially methylated regions (DMR) within <italic>GNAS</italic>.</p><p><bold>Results:</bold> Among the 88 subjects (median age 13.8 years, median body mass index Z-score +3.9), we identified one rare heterozygous missense variant of uncertain significance in the XL exon of <italic>GNAS</italic> in a single patient. We did not identify clearly pathogenic variants in <italic>PDE4D</italic> and <italic>PRKAR1A</italic>, and no <italic>GNAS</italic> methylation changes were detected by MS-MLPA.</p><p><bold>Conclusions:</bold> Our results suggest that coding <italic>GNAS</italic> mutations or methylation changes at the <italic>GNAS</italic> DMRs, or coding mutations in <italic>PDE4D</italic> and <italic>PRKAR1A</italic> are not common causes of isolated childhood obesity in Finland.</p>