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 earlyonset 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.

Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

“…1,2,11,14,16 Obesity or overweight is noted in 17 patients (10 of 14 patients with a deletion, 5 of 6 with a duplication, and 2 of 2 with a point mutation) and has an onset during (late) childhood (Supplementary Table S1 online). Other prevalent symptoms are a wide range of behavioral problems (11 of 14 patients with a deletion, 6 of 6 with a duplication, and 2 of 2 with a point mutation), such as aggressive, autistiform, and hyperactive behavior; stereotypic hand movements; and sleep disturbances.…”

“…[21][22][23] It was suggested that perturbed TMEM18 expression in the brain, and particularly in the hypothalamus, would translate into aberrant feeding behavior. Doco-Fenzy et al 2 and d' Angelo et al 16 reported a total of six patients carrying 2p25.3 deletions who had ID associated with obesity. It is interesting to note that in the five patients with a deletion reported by Doco-Fenzy et al, all deletions resided on the paternal allele, suggesting a paternal effect.…”

Mini-Review Prader-Willi-like phenotypes: a systematic review of their chromosomal abnormalities

“…If two or more articles reported the same chromosomal alterations for PW-like phenotype, the most recent was chosen. Twelve articles of 14 were case reports (Lukusa and Fryns, 2000;De Molfetta et al, 2002;Florez et al, 2003;Stalker et al, 2003;Niyazov et al, 2007;Nowicki et al, 2007;Gabbett et al, 2008;Pramyothin et al, 2010;Tsuyusaki et al, 2010;Ben-AbdallahBouhjar et al, 2012;Doco-Fenzy et al, 2013;Izumi et al, 2013) and two reported series of cases: one of 78 cases (Hosoki et al, 2009) and another of 9 cases (D'Angelo et al, 2013) ( Table 1). The patients included in this review were clinically diagnosed as bearing the PWlike phenotype because they were negative for alterations on 15q11-q13.…”

“…After the application of these techniques, the authors were able to exclude classical PWS, i.e., the syndrome caused by deficiency on 15q11-q13. They investigated further and discovered other mutations that could be associated with the PW-like phenotype, such as: a molecular pattern compatible with Angelman's syndrome (De Molfetta et al, 2002); chromosome 14 maternal uniparental disomy (Hosoki et al, 2009); monosomy of 1p36 (Tsuyusaki et al, 2010); deletion of 6q (Izume et al, 2013), 2pter deletion (Doco-Fenzy et al, 2013); and 10q26 deletion (Lukusa and Fryns, 2000); paracentric inversion (X)(q26q28) (Florez et al, 2003); 12q subtelomere deletions (Niyazov et al, 2007); Xq27-qter disomy; deletion 3p26.3 (Ben-Abdallah-Bouhjar et al, 2012); fragile X (Nowicki et al, 2007); and fragile X with 47,XYY (Stalker et al, 2003); deletion in 6q (Izumi et al, 2013); and Klinefelter syndrome karyotype, which showed a duplication of X(q21.1-q21.31) (Pramyothin et al, 2010) (Table 1). Recently, D'Angelo et al (2013) reported different copy number imbalances of chromosomes 2, 3, 6, 10, 12, 14, and X, in nine patients showing the PW-like phenotype.…”

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

“…A PWS-like phenotype, characterised by hypotonia, obesity, acromicria and variable motor, and cognitive delays, 3 has been reported in several conditions, such as maternal uniparental disomy for chromosome 14, 4,5 certain 1p36 deletions, 6,7 2p25 deletions, 8 Xq21 duplications, 9 Xq23q25 duplications, 10 and some cases of fragile X syndrome. 11,12 However, 6q16 deletion is the most common genetic abnormality in patients exhibiting the PWS-like phenotype.…”