PDF(Pubmed)
Abstract：
UNASSIGNED: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity.
UNASSIGNED: To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity.
UNASSIGNED: Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001).
UNASSIGNED: Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.
UNASSIGNED: To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity.
UNASSIGNED: Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001).
UNASSIGNED: Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.
摘要：
■常染色体显性遗传性多囊肾病（ADPKD）是最常见的单基因肾病，疾病严重程度具有惊人的家族变异性。
■为了更好地理解家族表型变异，我们分析了来自爱尔兰人群的92个无关ADPKD家族的临床和系谱数据,这些家族有≥2个患病个体(N=292).所有先证者都进行了基因测序。肾衰竭的发病年龄（KF），估计肾小球滤过率(eGFR)下降，多囊肾病（PROPKD）评分预测肾脏结局，和成像标准用于评估和分级疾病的严重程度为轻度，中间,或严重。每个家庭1例轻度和1例严重病例定义了疾病严重程度的明显家族内变异性。
■在92个家庭中至少有13％观察到明显的家族内变异性，携带PKD1非截短（PKD1-NT）变体的家族比例较高。在有≥2个成员受KF影响的家庭中，平均同龄年龄差异为7岁，等位基因组之间KF年龄的家族内变异性没有观察到差异。预先指定的标准显示显著的家族变异性为7.7%，8.4%,KF的年龄为24%，PROPKD评分,和成像标准，分别。在我们的多元混合效应模型中，肾脏生存率的家族内变异性与测得的与预后和生存率相关的基因型因素无关(P=<0.001).
■使用客观措施，我们量化了至少13%的家庭中ADPKD疾病表型的显著家族内变异性.我们的发现表明，家族内表型变异性仍未完全了解，因此需要更彻底地识别相关的临床和基因型因素。
■为了更好地理解家族表型变异，我们分析了来自爱尔兰人群的92个无关ADPKD家族的临床和系谱数据,这些家族有≥2个患病个体(N=292).所有先证者都进行了基因测序。肾衰竭的发病年龄（KF），估计肾小球滤过率(eGFR)下降，多囊肾病（PROPKD）评分预测肾脏结局，和成像标准用于评估和分级疾病的严重程度为轻度，中间,或严重。每个家庭1例轻度和1例严重病例定义了疾病严重程度的明显家族内变异性。
■在92个家庭中至少有13％观察到明显的家族内变异性，携带PKD1非截短（PKD1-NT）变体的家族比例较高。在有≥2个成员受KF影响的家庭中，平均同龄年龄差异为7岁，等位基因组之间KF年龄的家族内变异性没有观察到差异。预先指定的标准显示显著的家族变异性为7.7%，8.4%,KF的年龄为24%，PROPKD评分,和成像标准，分别。在我们的多元混合效应模型中，肾脏生存率的家族内变异性与测得的与预后和生存率相关的基因型因素无关(P=<0.001).
■使用客观措施，我们量化了至少13%的家庭中ADPKD疾病表型的显著家族内变异性.我们的发现表明，家族内表型变异性仍未完全了解，因此需要更彻底地识别相关的临床和基因型因素。
