■人口规模,具有关联电子健康记录(EHR)的外显子组测序队列允许基因组首先探索表型。表型和癌症风险在具有致病性DICER1(HGNCID:17098)变异的儿童中得到了很好的表征。这里,患病率,在两个人口规模队列中研究了成人致病性种系DICER1变异体的外显率和表型.
■在英国生物库(469,787个外显子组;无关:437,663)和Geisinger(170,503个外显子组;无关:109,789个)队列中,使用已发布的DICER1ClinGen标准对变异致病性进行分类。在英国生物银行队列中,EHR中的癌症诊断,对癌症和死亡登记进行了查询.对于Geisinger队列,对Geisinger癌症登记处和EHR进行了查询.
■在英国生物银行,在57例患者中有46种独特的致病性DICER1变异体(1:8,242;95CI:1:6,362-1:10,677).在Geisinger,21例患者中有16种独特的致病性DICER1变异(包括1种微缺失)(1:8,119;95CI:1:5,310-1:12,412).队列的功能很好,可以为常见的癌症找到更大的效果。癌症在DICER1杂合子中没有显著富集;然而,在两个队列中,甲状腺疾病的风险增加了约4倍.在两个队列中都有多个ICD10代码富集>2倍。
■致病性种系DICER1患病率的估计,在两个大型队列中确定了基因组确定的成年人的甲状腺疾病外显率和癌症表型。
UNASSIGNED: Population-scale, exome-sequenced cohorts with linked electronic health records (EHR) permit genome-first exploration of phenotype. Phenotype and cancer risk are well-characterized in children with a pathogenic
DICER1 (HGNC ID:17098) variant. Here, the prevalence, penetrance and phenotype of pathogenic germline DICER1 variants in adults was investigated in two population-scale cohorts.
UNASSIGNED: Variant pathogenicity was classified using published
DICER1 ClinGen criteria in the UK Biobank (469,787 exomes; unrelated: 437,663) and Geisinger (170,503 exomes; unrelated: 109,789) cohorts. In the UK Biobank cohort, cancer diagnoses in the EHR, cancer and death registry were queried. For the Geisinger cohort, the Geisinger Cancer Registry and EHR were queried.
UNASSIGNED: In the UK Biobank, there were 46 unique pathogenic
DICER1 variants in 57 individuals (1:8,242;95%CI:1:6,362-1:10,677). In Geisinger, there were 16 unique pathogenic DICER1 variants (including one microdeletion) in 21 individuals (1:8,119;95%CI:1:5,310-1:12,412). Cohorts were well-powered to find larger effect sizes for common cancers. Cancers were not significantly enriched in
DICER1 heterozygotes; however, there was a ~4-fold increased risk for thyroid disease in both cohorts. There were multiple ICD10 codes enriched >2-fold in both cohorts.
UNASSIGNED: Estimates of pathogenic germline
DICER1 prevalence, thyroid disease penetrance and cancer phenotype from genomically ascertained adults are determined in two large cohorts.