Table 2 Genomic regions and genes in the MLPA probe set

1q21.1

PRKAB2

Recurrent deletions and duplications at 1q21.1 are susceptibility factors for a variety of neurodevelopmental phenotypes. In one study, 6 out of 7 adults with 1q21.1 duplications had obesity or overweight and in 2 of 6 children with data, weight was above the 90th percentile. In another study, four patients were described with obesity and 1q21.1 deletions. Obesity was reported in four patients from DECIPHER (249137, 289048, 268066, and 249571) with duplication and in another (DECIPHER 290856) with deletion.

[43]-[45]

ACP6

2p25.3

ACP1

Deletions of 2pter are rare, and have often been associated with a PWS-like phenotype. The genes ACP1, TMEM18, and/or MYT1L were proposed as obesity candidates.

[9],[10],[21]

TPO

MYT1L

2q37.3

HDAC4

Deletions of the chromosome region 2q37 or mutation in the HDAC4 gene cause BDMR syndrome (obesity is seen in >40% of patients).

[3],[25]

GPR35

3p26.3

CNTN6

One patient described with syndromic obesity presenting with a 3pter deletion including only CNTN6 and CHL1 genes, both encoding neuronal adhesion molecules. Another patient with obesity reported in DECIPHER (249965) harboring an overlapping deletion in band 3p26.3.

[21]

CHL1

4p16.1

ACOX3

Williams et al. reported on a patient with a typical SMS phenotype showing obesity (SMS336) presenting with dup (4)(p16.1).

[58]

CPZ

6q16.3

SIM1

Obese patients presenting with a PWS-like phenotype and 6q16 deletions including SIM1. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. SIM1 is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus.

[6],[21],[50]

7q22.1

RELN

Two reports of 7q22 deletions in a patient presenting with syndromic obesity, and in another showing overgrowth and obesity.

[21],[59]

9q21.33

NTRK2

A heterozygous de novo mutation in NTRK2 was found in a child presenting with severe obesity, hyperphagia, and DD. NTRK2 is a highly specific receptor for BDNF, which makes its position within the leptin-melanocortin pathway evident.

[56],[57]

9q34.3

EHMT1

EHMT1 deletion (seen in >85% of cases) or mutation (rarely) causes KS. Obesity is present in a higher frequency in KS (~30-40%), and is more prevalent among patients with EHMT1 mutation than in patients with deletions (42 vs. 28%, respectively).

[30]

11p14.1

BDNF

Deletions extending the BDNF locus are associated with risk of obesity in a subgroup of patients with WAGR. Deletions outside of the WAGR region but spanning BDNF were reported in four patients with DD, behavioral problems, and obesity. Disruption of BDNF expression was associated with hyperphagia, obesity, and cognitive impairment in one published patient

[7],[14],[51]

MPPED2

12q15q21.1

PTPRB

Identical twins with deletion 12q15q21.1 presenting with syndromic obesity.

[21]

RAB21

TPH2

14q11.2

CHD8

Only one patient described with syndromic obesity presenting with a 14q11.2 microduplication encompassing SUPT16H and CHD8, highly expressed in adult and fetal brain, RAB2B, and two small nucleolar RNA (snoRNAs) [21].

[21]

RAB2B

14q12

PRKD1

Only one patient described with syndromic obesity presenting with a 14q12 microdeletion including only PRKD1 and a microRNA (MIR548AI) gene.

[21]

15q11.2

IPW

IPW is located to the critical region containing the functional PWS gene locus, and was found deleted in patients with atypical 15q11.2 deletions presenting the major features of PWS but normal methylation analysis.

[52]-[55]

16p11.2

CDIPT

The proximal 600-kb recurrent deletion within 16p11.2 confers susceptibility to autism and often cosegregates with early-onset obesity and neurodevelopmental disorders. The distal recurrent SH2B1-containing deletion within 16p11 was shown to account for 0.5% of severe childhood obese cases often co-occurring with DD. SH2B1 is involved in leptin and insulin signaling and is a solid candidate for obesity.

[16],[17]

MAPK3

SH2B

17p11.2

RAI1

Deletions of the chromosome region 17p11.2 or mutation in the RAI1 gene cause SMS. Obesity and hypercholesterolemia are phenotypes of SMS. RAI1 encodes a transcriptional regulator that directly regulates the expression of BDNF, a gene associated with obesity and hyperphagia. Bdnf was found downregulated in the hypothalamus of the mouse model for Rai1 haploinsufficiency.

[32]-[34]

22q11.2

CRKL

Obesity in patients from literature with deletions at both proximal and distal chromosome 22q11.2 intervals, and in patients from DECIPHER (2184, 2695, 248709, 250255, and 250888).

[37]-[42],[60]

MAPK1

RAB36