Two New Cases of 1p21.3 Deletions and an Unbalanced Translocation t(8;12) among Individuals with Syndromic Obesity

Abstract

due to duplication of the GNB3 gene. Thus, our findings add to the existing literature on the clinical description of these new syndromes, providing additional support that these loci are associated with syndromic obesity. We suggest that heterozygous loss of MIR137 may contribute to obesity as well as ID and ASD. AbstractObesity is a highly heritable but genetically heterogeneous disorder. Various well-known microdeletion syndromes (e.g. 1p36, 2q37, 6q16, 9q34, 17p11.2) can cause this phenotype along with intellectual disability (ID) and other findings. Chromosomal microarrays have identified 'new' microdeletion/duplication syndromes often associated with obesity. We report on 2 unrelated patients with an overlapping region of deletion at 1p21.3p21.2, and a third patient with a de novo recurrent unbalanced translocation der(8)t(8; 12) (p23.1;p13.31), detected by 180K array CGH in a prospective cohort of syndromic obesity patients. Deletion of 1p21.3 is a rare condition, and there have been only 11 cases of the same recurrent translocation between chromosomes 8 and 12 [t(8; 12)] reported to date. The former has been associated with ID, autistic spectrum disorder (ASD) and mild dysmorphic features, and in 4 patients who were obese or had a tendency to obesity, a minimal overlapping region of 2 genes, DPYD and MIR137 , was detected; t(8; 12) has recently been recognized to cause a childhood obesity syndrome

MIR137 is the key gene mediator of the syndromic obesity phenotype of patients with 1p21.3 microdeletions

“…Twelve patients carrying 1p21.3 deletions have been described in the literature to date [3–6], presenting with mild to moderate ID (100 %), obesity or a tendency to obesity, with a weight 3 or more standard deviations above the mean (92 %), ASD (92 %) and mild dysmorphic features (67 %) (Fig. 1 and Table 1).…”

“…The minimal overlapping region was restricted to a chromosomal segment of 1.22 Mb, which includes the DPYD and MIR137 genes. DPYD was proposed as the gene contributing to the phenotype [3, 5], based on the assumption that its haploinsufficiency would contribute to the development of a neuropsychiatric phenotype, which also leads to obesity. However, the case herein presented and the patient recently reported by Pinto et al [6] carried a deletion overlapping in the critical region only at the MIR137 , which suggests that this is the gene underlying the phenotype of patients carrying deletions at 1p21.3.

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“…Deletions in chromosome 1p21.3 have been reported in a total of 12 individuals presenting with a variable combination of ID, autism spectrum disorders (ASD) and obesity [3–6]. The shortest region of overlap (SRO) has been restricted to two genes: dihydropyrimidine dehydrogenase ( DPYD ) and microRNA 137 ( MIR137 ).…”

Genome sequencing reveals a novel genetic mechanism underlying dihydropyrimidine dehydrogenase deficiency: A novel missense variant c.1700G>A and a large intragenic inversion in DPYD spanning intron 8 to intron 12

“…Previously, we showed that genomic deletions affecting DPYD occurred in 7% of pediatric patients with a complete DPD deficiency (van Kuilenburg et al., ). Genomic rearrangements in DPYD have also been observed in patients with ID (Willemsen et al., ), autism‐spectrum disorder (Carter et al., ; Prasad et al., ), syndromic obesity (D'Angelo, Moller Dos Santos, Alonso, & Koiffmann, ), and amyotrophic lateral sclerosis (Uyan et al., ). To date, no clear genotype–phenotype correlation has been established in patients with a DPD deficiency but it is noteworthy that patients with gross deletions in DPYD presented with a severe phenotype when compared with that observed in other DPD patients (van Kuilenburg et al., ).…”

Integrated Transcriptome Analyses Revealed Key Target Genes in Mouse Models of Autism

“…The following information on included studies was collected: first author, gene symbol, age of mice, analyzed brain region, test platform, database, and project number. With all above, the major clinical information related to these mutant genes was collected from OMIM database and several reviews [Carratala-Marco et al, 2018;D'Angelo, Moller, Alonso, & Koiffmann, 2015;Geets, Meuwissen, & Van Hul, 2019;Merner et al, 2016;Tucci, Ciaccio, Scuvera, Esposito, & Milani, 2016].…”