Background

Leukodystrophies are genetic diseases affecting the white matter and leading to early death. Our objective was to determine leukodystrophy incidence, using genomics sequencing databases allele frequencies of disease-causing variants.

Methods

From 49 genes, representing the standardly defined group of leukodystrophies, we identified potential disease-causing variants from publications in the Human Genetic Mutation Database and from predictions in the Genome Aggregation Database. Allele frequencies were estimated from Genome Aggregation Database. Allele frequencies for each gene were summed to generate a super allele frequency and we used the Hardy-Weinberg equation to calculate overall expected live birth incidence associated with the gene in question.

Results

We identified 4564 pathogenic variants for 25 discrete leukodystrophies. The largest effect was from GALC variants (Krabbe disease), which had a predicted incidence of one in 12,080 live births, 8.3 times higher than published estimates. The second most frequently predicted leukodystrophy was the RNA polymerase III–related disorders, which had an incidence of 1:26,160. Overall, we found a leukodystrophy incidence of 1 in 4733 live births, significantly higher than previous estimates.

Conclusions

Our data are consistent with a significant underdiagnosis of leukodystrophy patients. An intriguing additional consideration is that there may be genetic modifiers that lead to weaker, absent, or adult-onset disease phenotypes.

中文翻译：

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从基因组学数据库预测的脑白质营养不良发病率升高。

背景

脑白质营养不良是影响白质并导致过早死亡的遗传性疾病。我们的目标是使用基因组测序数据库中致病变异的等位基因频率来确定脑白质营养不良的发生率。

方法

从代表标准定义的脑白质营养不良组的 49 个基因中，我们从人类遗传突变数据库的出版物和基因组聚合数据库的预测中确定了潜在的致病变异。从基因组聚合数据库估计等位基因频率。将每个基因的等位基因频率相加以生成超等位基因频率，我们使用 Hardy-Weinberg 方程计算与相关基因相关的总体预期活产发生率。

结果

我们确定了 25 种离散脑白质营养不良的 4564 个致病变异。最大的影响来自GALC变异（克拉伯病），其预测的发病率为 12,080 名活产婴儿中的 1 名，比公布的估计值高 8.3 倍。第二个最常预测的脑白质营养不良是 RNA 聚合酶 III 相关疾病，其发生率为 1:26,160。总体而言，我们发现 4733 名活产婴儿中脑白质营养不良的发生率为 1 例，显着高于之前的估计。

结论

我们的数据与脑白质营养不良患者的严重漏诊相一致。一个有趣的额外考虑是，可能存在导致较弱、缺失或成人发病的疾病表型的遗传修饰物。