Abstract：
Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease.
We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points.
Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication.
Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.
We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points.
Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication.
Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.
摘要：
目的：常染色体显性遗传多囊性肝病（ADPLD）是一种罕见的女性优势疾病，主要基于两个基因的致病变异，PRKCSH和SEC63。临床上,ADPLD的特点是巨大的异质性，从无症状到高度症状的肝肿大。迄今为止,对早期疾病进展的预测知之甚少，阻碍临床管理，遗传咨询,和随机对照试验的设计。为了改善疾病预后，我们建立了一个欧洲和美国中心联盟,以招募最大的PRKCSH和SEC63肝病患者队列.
方法：我们分析了一个由265例携带PRKCSH或SEC63致病变异的ADPLD患者组成的多中心队列的基因型-表型相关性，包括标准化的年龄校正的总肝脏体积(nTLV)和PLD相关住院(肝脏事件)作为主要临床终点.
结果：将个体nTLV分类为预定义的进展组，可预测未来肝脏事件的风险区分，与性别和潜在的遗传缺陷无关。此外,疾病严重程度,由第一次肝脏事件的年龄定义，在女性和PRKCSH变异的患者中，比SEC63变异的患者更明显。新开发的性别基因评分可有效区分轻度，中度,和严重的疾病，除了基于成像的预后。
结论：影像学和临床遗传评分都有可能告知患者一生中发生症状性疾病的风险。女性的结合，种系PRKCSH改变，快速的TLV进展与PLD相关住院的最大几率相关。
方法：我们分析了一个由265例携带PRKCSH或SEC63致病变异的ADPLD患者组成的多中心队列的基因型-表型相关性，包括标准化的年龄校正的总肝脏体积(nTLV)和PLD相关住院(肝脏事件)作为主要临床终点.
结果：将个体nTLV分类为预定义的进展组，可预测未来肝脏事件的风险区分，与性别和潜在的遗传缺陷无关。此外,疾病严重程度,由第一次肝脏事件的年龄定义，在女性和PRKCSH变异的患者中，比SEC63变异的患者更明显。新开发的性别基因评分可有效区分轻度，中度,和严重的疾病，除了基于成像的预后。
结论：影像学和临床遗传评分都有可能告知患者一生中发生症状性疾病的风险。女性的结合，种系PRKCSH改变，快速的TLV进展与PLD相关住院的最大几率相关。
