Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
J Am Soc Nephrol. 2018 Oct;29(10):2593-2600. doi: 10.1681/ASN.2018050493. Epub 2018 Aug 22.
Estimating the prevalence of autosomal dominant polycystic kidney disease (ADPKD) is challenging because of age-dependent penetrance and incomplete clinical ascertainment. Early studies estimated the lifetime risk of ADPKD to be about one per 1000 in the general population, whereas recent epidemiologic studies report a point prevalence of three to five cases per 10,000 in the general population.
To measure the frequency of high-confidence mutations presumed to be causative in ADPKD and autosomal dominant polycystic liver disease (ADPLD) and estimate lifetime ADPKD prevalence, we used two large, population sequencing databases, gnomAD (15,496 whole-genome sequences; 123,136 exome sequences) and BRAVO (62,784 whole-genome sequences). We used stringent criteria for defining rare variants in genes involved in ADPKD (, ), ADPLD (, , , , , ), and potential cystic disease modifiers; evaluated variants for quality and annotation; compared variants with data from an ADPKD mutation database; and used bioinformatic tools to predict pathogenicity.
Identification of high-confidence pathogenic mutations in whole-genome sequencing provided a lower boundary for lifetime ADPKD prevalence of 9.3 cases per 10,000 sequenced. Estimates from whole-genome and exome data were similar. Truncating mutations in ADPLD genes and genes of potential relevance as cyst modifiers were found in 20.2 cases and 103.9 cases per 10,000 sequenced, respectively.
Population whole-genome sequencing suggests a higher than expected prevalence of ADPKD-associated mutations. Loss-of-function mutations in ADPLD genes are also more common than expected, suggesting the possibility of unrecognized cases and incomplete penetrance. Substantial rare variation exists in genes with potential for phenotype modification in ADPKD.
由于年龄依赖性外显率和不完全的临床确定，估计常染色体显性多囊肾病（ADPKD）的患病率具有挑战性。早期研究估计，一般人群中 ADPKD 的终生风险约为每 1000 人中有 1 例，而最近的流行病学研究报告称，一般人群中每 10000 人中就有 3 至 5 例 ADPKD 病例。
为了测量被认为是 ADPKD 和常染色体显性多囊肝病（ADPLD）的致病的高置信突变的频率，并估计 ADPKD 的终生患病率，我们使用了两个大型的人群测序数据库，gnomAD（15496 个全基因组序列；123136 个外显子组序列）和 BRAVO（62784 个全基因组序列）。我们使用严格的标准来定义与 ADPKD（PKD1、PKD2、PKHD1、ACTA2、LRP5、IFT140）、ADPLD（PRKCSH、BBS1、BBS2、BBS4、TMEM67、IFT140）和潜在的囊性疾病修饰因子相关的基因中的稀有变异；评估变异的质量和注释；将变异与 ADPKD 突变数据库中的数据进行比较；并使用生物信息学工具来预测致病性。
全基因组测序中高置信度的致病突变的鉴定为每 10000 个测序个体中终生 ADPKD 的患病率提供了一个下限，为 9.3 例。全基因组和外显子组数据的估计值相似。ADPLD 基因和潜在的囊性疾病修饰因子相关基因中的截断突变分别在每 10000 个测序个体中发现 20.2 例和 103.9 例。
人群全基因组测序表明，与 ADPKD 相关的突变的患病率高于预期。ADPLD 基因中的功能丧失突变也比预期的更常见，这表明可能存在未被识别的病例和不完全外显率。在 ADPKD 中具有表型修饰潜力的基因中存在大量的罕见变异。
