BackgroundMutations in the leptin gene (LEP) can alter the secretion or interaction of leptin with its receptor, leading to extreme early-onset obesity. The purpose of this work was to estimate the prevalence of heterozygous and homozygous mutations in the leptin gene with the help of the Exome Aggregation Consortium (ExAC) database (http://exac.broadinstitute.org/about).ResultsThe ExAC database encompasses exome sequencing data from 60,706 individuals. We searched for listed leptin variants and identified 36 missense, 1 in-frame deletion, and 3 loss-of-function variants. The functional relevance of these variants was assessed by the in silico prediction tools PolyPhen-2, Sorting Intolerant from Tolerant (SIFT), and Loss-Of-Function Transcript Effect Estimator (LOFTEE). PolyPhen-2 predicted 7 of the missense variants to be probably damaging and 10 to be possibly damaging. SIFT predicted 7 of the missense variants to be deleterious. Three loss-of-function variants were predicted by LOFTEE. Excluding double counts, we can summarize 21 variants as potentially damaging. Considering the allele count, we identified 31 heterozygous but no homozygous subjects with at least probably damaging variants. In the ExAC population, the estimated prevalence of heterozygous carriers of these potentially damaging variants was 1:2000. The probability of homozygosity was 1:15,000,000.We furthermore tried to assess the functionality of ExAC-listed leptin variants by applying a knowledge-driven approach. By this approach, additional 6 of the ExAC-listed variants were considered potentially damaging, increasing the number of heterozygous subjects to 58, the prevalence of heterozygosity to 1:1050, and the probability of homozygosity to 1:4,400,000.ConclusionUsing exome sequencing data from ExAC, in silico prediction tools and by applying a knowledge-driven approach, we identified 27 probably damaging variants in the leptin gene of 58 heterozygous subjects. With this information, we estimate the prevalence for heterozygosity at 1:1050 corresponding to an prevalence of homozygosity of 1:4,400,000 in this large pluriethnic cohort.

中文翻译：

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瘦素基因中潜在破坏性变异的估计流行率

背景瘦素基因 (LEP) 中的突变可以改变瘦素与其受体的分泌或相互作用，导致极度早发性肥胖。这项工作的目的是在外显子组聚合联盟 (ExAC) 数据库 (http://exac.broadinstitute.org/about) 的帮助下估计瘦素基因中杂合和纯合突变的流行率。 结果 ExAC 数据库包含外显子组来自 60,706 个人的测序数据。我们搜索了列出的瘦素变体，并确定了 36 个错义、1 个框内缺失和 3 个功能缺失变体。这些变体的功能相关性通过计算机预测工具 PolyPhen-2、从耐受性排序不耐受 (SIFT) 和功能损失转录效果估计器 (LOFTEE) 进行评估。PolyPhen-2 预测 7 个错义变体可能具有破坏性，10 个可能具有破坏性。SIFT 预测 7 个错义变体是有害的。LOFTEE 预测了三种功能丧失变体。排除重复计数，我们可以将 21 个变体总结为具有潜在破坏性。考虑到等位基因计数，我们确定了 31 个杂合子，但没有纯合子受试者至少可能具有破坏性变异。在 ExAC 人群中，这些潜在破坏性变异的杂合子携带者的估计流行率为 1:2000。纯合子的概率为 1:15,000,000。此外，我们还尝试通过应用知识驱动的方法来评估 ExAC 列出的瘦素变体的功能。通过这种方法，ExAC 列出的另外 6 个变体被认为具有潜在破坏性，将杂合子受试者的数量增加到 58 个，杂合子的流行率增加到 1:1050，纯合子的概率增加到 1:4,400,000。结论使用来自 ExAC 的外显子组测序数据、计算机预测工具并通过应用知识驱动的方法，我们确定58 个杂合子受试者的瘦素基因中有 27 个可能具有破坏性的变异。有了这些信息，我们估计了 1:1050 的杂合性流行率，对应于这个大型多民族队列中 1:4,400,000 的纯合性流行率。我们在 58 个杂合子受试者的瘦素基因中发现了 27 个可能具有破坏性的变异。有了这些信息，我们估计了 1:1050 的杂合性流行率，对应于这个大型多民族队列中 1:4,400,000 的纯合性流行率。我们在 58 个杂合子受试者的瘦素基因中发现了 27 个可能具有破坏性的变异。有了这些信息，我们估计了 1:1050 的杂合性流行率，对应于这个大型多民族队列中 1:4,400,000 的纯合性流行率。