BioMarin Pharmaceutical, San Rafael, CA, United States of America.
PLoS One. 2018 Jul 6;13(7):e0200008. doi: 10.1371/journal.pone.0200008. eCollection 2018.
Given the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested this idea on a rare, monogenic, lysosomal storage disorder, Sanfilippo Type B (Mucopolysaccharidosis type IIIB). Sanfilippo Type B is caused by mutations in the gene encoding α-N-acetylglucosaminidase (NAGLU). There were 189 NAGLU missense variants found in the ExAC dataset that comprises roughly 60,000 individual exomes. Only 24 of the 189 missense variants were known to be pathogenic; the remaining 165 variants were of unknown significance (VUS), and their potential contribution to disease is unknown. To address this problem, we measured enzymatic activities of 164 NAGLU missense VUS in the ExAC dataset and developed a statistical framework for estimating disease incidence with associated confidence intervals. We found that 25% of VUS decreased the activity of NAGLU to levels consistent with Sanfilippo Type B pathogenic alleles. We found that a substantial fraction of Sanfilippo Type B incidence (67%) could be accounted for by novel mutations not previously identified in patients, illustrating the utility of combining functional activity data for VUS with population-wide allele frequency data in estimating disease incidence.
鉴于大量且不断扩大的公共测序数据，只要知道哪些突变是致病的，就应该有可能从等位基因频率中提取单基因疾病的发病率信息。我们在一种罕见的单基因溶酶体贮积症 Sanfilippo 型 B（黏多糖贮积症 IIIB）上测试了这个想法。Sanfilippo 型 B 是由编码α-N-乙酰氨基葡萄糖苷酶（NAGLU）的基因突变引起的。在包含大约 60,000 个个体外显子的 ExAC 数据集中共发现了 189 种 NAGLU 错义变异，其中只有 24 种错义变异被认为是致病性的；其余 165 种变异为意义不明（VUS），其对疾病的潜在贡献尚不清楚。为了解决这个问题，我们测量了 ExAC 数据集中 164 种 NAGLU 错义 VUS 的酶活性，并开发了一种统计框架，用于估计疾病发病率及其相关置信区间。我们发现，25%的 VUS 降低了 NAGLU 的活性，使其与 Sanfilippo 型 B 的致病等位基因一致。我们发现，相当一部分 Sanfilippo 型 B 的发病率（67%）可以归因于以前在患者中未发现的新突变，这说明了将 VUS 的功能活性数据与全人群等位基因频率数据相结合用于估计疾病发病率的实用性。
