Copy number variants are enriched in individuals with early-onset obesity and highlight novel pathogenic pathways
M Pettersson, H Viljakainen, P Loid… - The Journal of …, 2017 - academic.oup.com
M Pettersson, H Viljakainen, P Loid, T Mustila, M Pekkinen, M Armenio…
The Journal of Clinical Endocrinology & Metabolism, 2017•academic.oup.comContext Only a few genetic causes for childhood obesity have been identified to date. Copy
number variants (CNVs) are known to contribute to obesity, both syndromic (15q11. 2
deletions, Prader-Willi syndrome) and nonsyndromic (16p11. 2 deletions) obesity. Objective
To study the contribution of CNVs to early-onset obesity and evaluate the expression of
candidate genes in subcutaneous adipose tissue. Design and Setting A case-control study
in a tertiary academic center. Participants CNV analysis was performed on 90 subjects with …
number variants (CNVs) are known to contribute to obesity, both syndromic (15q11. 2
deletions, Prader-Willi syndrome) and nonsyndromic (16p11. 2 deletions) obesity. Objective
To study the contribution of CNVs to early-onset obesity and evaluate the expression of
candidate genes in subcutaneous adipose tissue. Design and Setting A case-control study
in a tertiary academic center. Participants CNV analysis was performed on 90 subjects with …
Context
Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity.
Objective
To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue.
Design and Setting
A case-control study in a tertiary academic center.
Participants
CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses.
Main Outcome Measures
We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue.
Results
We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5).
Conclusions
Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.
Oxford University Press