Early-onset obesity and paternal 2pter deletion encompassing the ACP1, TMEM18, and MYT1L genes

Abstract

Obesity is a common but highly, clinically, and genetically heterogeneous disease. Deletion of the terminal region of the short arm of chromosome 2 is rare and has been reported in about 13 patients in the literature often associated with a Prader-Willi-like phenotype. We report on five unrelated patients with 2p25 deletion of paternal origin presenting with early-onset obesity, hyperphagia, intellectual deficiency, and behavioural difficulties. Among these patients, three had de novo pure 2pter deletions, one presented with a paternal derivative der(2)t(2;15)(p25.3;q26) with deletion in the 2pter region and the last patient presented with an interstitial 2p25 deletion. The size of the deletions was characterized by SNP array or array-CGH and was confirmed by fluorescence in situ hybridization (FISH) studies. Four patients shared a 2p25.3 deletion with a minimal critical region estimated at 1.97 Mb and encompassing seven genes, namely SH3HYL1, ACP1, TMEMI8, SNTG2, TPO, PXDN, and MYT1L genes. The fifth patient had a smaller interstitial deletion encompassing the TPO, PXDN, and MYT1L genes. Paternal origin of the deletion was determined by genotyping using microsatellite markers. Analysis of the genes encompassed in the deleted region led us to speculate that the ACP1, TMEM18, and/or MYT1L genes might be involved in early-onset obesity. In addition, intellectual deficiency and behavioural troubles can be explained by the heterozygous loss of the SNTG2 and MYT1L genes. Finally, we discuss the parent-of-origin of the deletion.

Figures

Figure 1

(a) On the left growth curves for patients 1–5 showing the early-onset obesity and on the right BMI graphs for patients 1–5. (b) Pictures of patients 1 and 4–5 showing the facial features. Patients 1 and 4 have thin eyebrows, downslanting palpebral fissures, small nose with upturned nostrils, small mouth, thin lips, and obesity. Patient 2 has horizontal palpebral fissures, frontal bossing, short philtrum, and everted upper lip.

Figure 2

(a) Array-CGH screen shot for patient 4 showing the distal 2p deletion encompassing the subtelomeric region to the MYT1L gene. (b) Genotyping analysis for patient 3 with D2S323 STS showing the absence of the paternal allele for the Child on the second line (C) compared with Mother (M) and Father (F). (c) FISH metaphase for patient 1 with commercial subtelomeric 2p (green-FITC) and 2q (red-CY3) probes showing no green signal on the deleted 2p region.

Figure 3

Screen shot UCSC Hg19 Built 37 showing a summary of the deleted segments of patients 1–5 and the reported patients from Decipher, Stevens et al, and Rio et al. (a) Correlation map for obesity. In dark grey the obese patients and in middle grey the overweight patients. SRO: smallest region of overlap. (b) Correlation map for behavioural troubles. In dark grey, patients with aggressiveness or outbursts. In middle grey, patients with behavioural troubles missing aggressiveness. In light grey, no reported behavioural troubles. ASD: at least one feature in autism spectrum.