Background

Previous estimates of the prevalence of Menkes disease, a lethal X-linked recessive disorder of copper metabolism, were based on confirmed clinical cases ascertained from specific populations and varied from 1 in 40,000 to 1 in 354,507. With newly available population-based allelic frequencies of DNA sequence variants, the expected birth prevalence of Menkes disease and other ATP7A-related phenotypes can be reconsidered using Hardy-Weinberg theoretical principles.

Methods

We reviewed the canonical ATP7A transcript in the current version of gnomAD (v2.1.1) to evaluate frequency of complete loss-of-function alleles in a diverse normal control population. As a comparator, we used the DMD locus, associated with Duchenne and Becker Muscular Dystrophy, another X-linked recessive trait. We applied Hardy-Weinberg theory and PolyPhen-2 in silico plus REVEL and CADD ensemble analyses to calculate estimated frequencies of normal and predicted deleterious ATP7A alleles.

Results

We identified 1106 total ATP7A variants out of 205,523 alleles in gnomAD, with missense variants most common (43.4%). Complete loss-of-function variants were found in four ATP7A alleles (frequency = 0.0000194), including three frameshift/nonsense mutations and one canonical splice donor site defect. Assuming Hardy-Weinberg equilibrium, this frequency of pathogenic alleles predicts 1 in 34,810 live male births with Menkes disease or other ATP7A-related disorders each year in the US. The same analysis for DMD loss-of-function variants predicted 1 in 7246 newborn males with Duchenne (or Becker) muscular dystrophy. We also identified nine ATP7A missense variants in gnomAD predicted as deleterious by PolyPhen-2 and stringent REVEL/CADD criteria, comprising 12 more disease-causing alleles and raising the estimated birth prevalence to 1 in 8664 and predicting 225 newborns with Menkes disease or other ATP7A-related disorders per year in the US alone.

Conclusions

Assuming Hardy-Weinberg equilibrium, the allelic frequency of deleterious ATP7A variants in a genomic database from a large diverse population predicts a birth prevalence of Menkes disease or ATP7A-related disorders as high as 1 in 8664 live male births. This genome-driven ascertainment of deleterious ATP7A alleles in the population implies a higher birth prevalence of Menkes disease and ATP7A-related conditions than previously appreciated. A population-based newborn screening pilot study for Menkes disease will be instrumental in confirming the prediction.

中文翻译：

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根据基因组聚合数据库 (gnomAD) 估计门克斯病和 ATP7A 相关疾病的出生患病率。

背景

此前对门克斯病（一种致命的 X 连锁隐性铜代谢疾病）患病率的估计是基于从特定人群中确定的确诊临床病例，从 40,000 分之一到 354,507 分之一不等。利用新获得的基于人群的 DNA 序列变异等位基因频率，可以使用 Hardy-Weinberg 理论原理重新考虑Menkes 病和其他ATP 7 A相关表型的预期出生流行率。

方法

我们回顾了当前版本的 gnomAD (v2.1.1) 中的规范ATP 7 A转录本，以评估不同正常对照人群中完全功能丧失等位基因的频率。作为比较，我们使用了与杜氏肌营养不良症和贝克尔肌营养不良症（另一种 X 连锁隐性特征）相关的DMD基因座。我们应用 Hardy-Weinberg 理论和 PolyPhen-2 in silico加上 REVEL 和 CADD 整体分析来计算正常和预测的有害ATP 7 A等位基因的估计频率。

结果

我们从 gnomAD 的 205,523 个等位基因中总共鉴定出了 1106 个ATP 7 A变体，其中错义变体最常见 (43.4%)。在 4 个ATP 7 A等位基因中发现了完全功能丧失的变异（频率 = 0.0000194），包括 3 个移码/无义突变和 1 个典型剪接供体位点缺陷。假设哈迪-温伯格平衡，这种致病等位基因的频率预测在美国每年 34,810 名活产男性中就有 1 人患有门克斯病或其他 ATP7A 相关疾病。对DMD功能丧失变异的相同分析预测，7246 名新生儿男性中就有 1 人患有杜氏（或贝克尔）肌营养不良症。我们还鉴定了 gnomAD 中的 9 个ATP 7 A错义变异，经 PolyPhen-2 和严格的 REVEL/CADD 标准预测为有害，其中包含 12 个以上致病等位基因，并将估计出生率提高到 8664 分之一，并预测 225 名新生儿患有门克斯病或仅在美国每年就有其他 ATP7A 相关疾病发生。

结论

假设 Hardy-Weinberg 平衡，来自大量不同人群的基因组数据库中有害ATP 7 A变体的等位基因频率预测，门克斯病或 ATP7A 相关疾病的出生患病率高达每 8664 名活男性新生儿中就有 1 例。这种基因组驱动的对人群中有害 ATP7A 等位基因的确定意味着门克斯病和 ATP7A 相关疾病的出生患病率比之前估计的要高。基于人群的门克斯病新生儿筛查试点研究将有助于证实这一预测。