D'Angelo Carla Sustek, Varela Monica Castro, de Castro Claudia Irene Emílio, Otto Paulo Alberto, Perez Ana Beatriz Alvarez, Lourenço Charles Marques, Kim Chong Ae, Bertola Debora Romeo, Kok Fernando, Garcia-Alonso Luis, Koiffmann Celia Priszkulnik
1Human Genome and Stem Cell Research Center (HUG-CELL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Rua do Matao no 277, Cidade Universitaria-Butanta, Sao Paulo, SP 05508-090 Brazil.
2Department of Morphology and Genetics, Paulista School of Medicine, Federal University of Sao Paulo (UNIFESP), Sao Paulo, SP Brazil.
Mol Cytogenet. 2018 Feb 5;11:14. doi: 10.1186/s13039-018-0363-7. eCollection 2018.
Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype.
Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility . We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. , , , , , ), and also identified other potentially relevant candidates including , , and
Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.
综合征性肥胖是一个概括性术语，用于描述肥胖与其他表型同时出现的情况。它通常作为一种独特的遗传综合征的一部分出现，普拉德-威利综合征就是一个典型例子。这些罕见的肥胖形式为识别肥胖相关的基因变化提供了独特来源。染色体微阵列分析（CMA）已使综合征性肥胖的新遗传形式得以表征，这些形式归因于拷贝数变异（CNV）；然而，对大型队列进行CMA还需要更多研究。本研究的目的是表征在279例具有综合征性肥胖表型的患者中通过CMA检测到的CNV。
在61例患者（22%）中检测到致病性CNV，其中35例具有重叠/复发性CNV。在8.2%的病例中发现了已知会导致综合征性肥胖的基因组失衡疾病，最常见的是1p36、2q37和17p11.2缺失（5.4%），我们还检测到1p21.3、2p25.3、6q16、9q34、16p11.2远端和近端的缺失，以及导致一种儿童肥胖综合征相关基因重复的不平衡易位。9p末端和22q11.2近端/远端缺失分别在1%和3%的病例中被发现。因此，它们成为新的假定肥胖易感性因素。我们在研究中发现了其他与先前报道的综合征性肥胖病例中的CNV重叠的CNV，包括一例新的13q34缺失（），使与肥胖相关的此类缺陷患者数量增至7例。我们的发现涉及许多先前与肥胖相关的基因（如 、 、 、 、 、 ），还鉴定出了其他潜在相关候选基因，包括 、 、 和 。
事实证明，了解肥胖的遗传学很困难，而从对作为表型一部分与肥胖相关的基因组疾病的研究中已获得了相当多的见解。在我们的研究中，8.2%的患者检测到已知是综合征性肥胖病因的CNV，但我们为多达14%的病例提供了肥胖遗传基础的证据。总体而言，我们的结果强调了综合征性肥胖形式中的遗传异质性，这对诊断构成了重大挑战。
