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23-12-2009 | Cardiometabolic | Article

Large, rare chromosomal deletions linked to severe early-onset obesity


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MedWire News: Large, rare chromosomal deletions contribute significantly to the genetic element of severe obesity, say researchers.

They found that chromosomal deletions larger than 500 kilobases (kb) and present in less than 1% of individuals were significantly enriched in patients with severe early-onset obesity, particularly those who also had developmental delay.

Previous studies have identified common single nucleotide polymorphisms associated with increased body mass index (BMI), but these account for only a small percentage of the inherited variation in BMI.

To explore the contribution of copy number variants (CNVs) to obesity, a British team led by Elena Bochukova, from Addenbrooke’s Hospital in Cambridge, and Ni Huang, from the Wellcome Trust Sanger Institute in Cambridgeshire studied 300 Caucasians with severe early-onset obesity, 143 of whom also had developmental delay.

The researchers report that several rare CNVs were recurrent in the severely obese participants, but were rare or significantly less prevalent in a group of 7366 non-obese control individuals.

They identified five patients with overlapping deletions on chromosome 16p11.2 that were found in only two of the controls. In three patients the deletion co-segregated with severe obesity.

Two obese patients carried a larger de novo 16p11.2 deletion, extending through a 593-kilobase region previously associated with autism and mental retardation, and both of these patients had mild developmental delay in addition to severe obesity.

In an independent sample of 1062 patients with severe obesity alone, the smaller 16p11.2 deletion was found in an additional two patients. All 16p11.2 deletions encompass several genes but include SH2B1, which is known to be involved in leptin and insulin signaling.

Writing in the journal Nature, the researchers conclude: “CNV contributes significantly to the genetic architecture of human obesity.”

They add: “Deletion of 16p11.2 is associated with highly penetrant familial severe early-onset obesity and severe insulin resistance… the phenotype is consistent with a role for SH2B1 in human energy homeostasis and glucose metabolism.”

MedWire ( is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

By Joel Levy