Manco Licínio, Pereira Janet, Fidalgo Teresa, Cunha Marina, Pinto-Gouveia José, Padez Cristina, Palmeira Lara
Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Portugal.
Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, Portugal; Department of Clinical Hematology, Centro Hospitalar e Universitário de Coimbra, Portugal.
Eur J Med Genet. 2023 Apr;66(4):104728. doi: 10.1016/j.ejmg.2023.104728. Epub 2023 Feb 10.
We examined 12 monogenic obesity genes in 72 Portuguese individuals with overweight and obesity (class 1 and class 2), some of which with suspected genetic obesity, to identify known or unknown potential obesity variants. Genomic DNA was analyzed for variants in genes LEP, LEPR, MC4R, POMC, PCSK1, BDNF, NTRK2, SIM1, SH2B1, UCP3, GCG and ADCY3 through next generation sequencing (NGS). The impact of the rare variants was investigated in the ClinVar database and using in silico tools for prediction of pathogenicity. Four potential pathogenic missense variants were detected at the heterozygous state in five individuals: two in the ADCY3 gene, NM_004036.5:c.1153G > A (p.Val385Ile) (rs756783003) and NM_004036.5:c.1222G > A (p.Gly408Arg) (rs201606553), one in gene SH2B1, NM_001145795.1:c.127C > A (p.Arg43Ser) (rs547678855), and the fourth in gene POMC NM_000939.4:c.706C > G (p.Arg236Gly) (rs28932472), which was found in two individuals. Moreover, six rare variants near splicing sites were also identified, as well as eight rare synonymous variants. In summary, some potential pathogenic rare missense variants were identified, two of them in ADCY3 gene, the most recently identified gene as having a role in monogenic obesity. Further analysis should be performed to confirm the clinical relevance of these variants.
我们对72名超重和肥胖（1级和2级）的葡萄牙个体进行了12个单基因肥胖基因检测，其中一些人疑似患有遗传性肥胖，以确定已知或未知的潜在肥胖变异。通过下一代测序（NGS）分析基因组DNA中LEP、LEPR、MC4R、POMC、PCSK1、BDNF、NTRK2、SIM1、SH2B1、UCP3、GCG和ADCY3基因的变异。在ClinVar数据库中调查了罕见变异的影响，并使用计算机工具预测其致病性。在5名个体中检测到4个潜在的致病性错义变异，均为杂合状态：ADCY3基因中的两个，分别为NM_004036.5:c.1153G>A（p.Val385Ile）（rs756783003）和NM_004036.5:c.1222G>A（p.Gly408Arg）（rs201606553）；SH2B1基因中的一个，为NM_001145795.1:c.127C>A（p.Arg43Ser）（rs547678855）；POMC基因中的第四个，为NM_000939.4:c.706C>G（p.Arg236Gly）（rs28932472），在两名个体中发现。此外，还鉴定出6个剪接位点附近的罕见变异以及8个罕见同义变异。总之，鉴定出了一些潜在的致病性罕见错义变异，其中两个在ADCY3基因中，该基因是最近确定的在单基因肥胖中起作用的基因。应进行进一步分析以确认这些变异的临床相关性。
