Purpose

To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020).

Methods

All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing.

Results

Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%).

Conclusion

We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.

中文翻译：

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亚型 PKD1 变体的双等位基因遗传在极早发的多囊肾病中非常普遍

目的

在 10 年期间（2010-2020 年）因临床适应症转诊的大型国际儿科队列中，调查极早发 (VEO) 多囊肾病 (PKD)双等位基因PKD1和PKD2变异的流行率。

方法

所有样本均通过PKD1和PKD2基因的 Sanger 测序和多重连接依赖性探针扩增 (MLPA)和/或 15 个额外囊性基因（包括PKHD1和HNF1B ）的下一代测序组进行测试。两名患者接受了外显子组或基因组测序。

结果

在 30 名 PKD-VEO 婴儿中检测到可能致病的PKD1 或 PKD2变异，其中 16 名在子宫内出现。30 人中有 21 人 (70%)在 16/21 中确认了两个具有双等位基因的反式遗传变异，1 名婴儿具有双等位基因PKD2变异，2 名婴儿具有双基因PKD1/PKD2变异。13 个家庭 (43%) 没有已知的 ADPKD 家族史，6 个家庭 (23%) 确认有新发致病性变异。

结论

我们报告了患有 PKD-VEO 的婴儿中亚型PKD1变体和可能的双等位基因疾病的高患病率，这对生殖咨询具有重要意义。然而，使用当前美国医学遗传学和基因组学学院/分子病理学协会 (ACMG/AMP) 和临床遗传科学协会 (ACGS) 对 PKD-VEO 和其他受影响疾病的变异分类指南，对这些变异的诊断解释和报告仍然具有挑战性通过具有不完全外显率的类似变体。