Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.
Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.
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DOI：
10.1038/s41436-020-01026-4
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发表时间：
2021-04
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研究10年期间（2010-2020年）因临床适应症转诊的一个大型国际儿科队列中，作为极早发型（VEO）多囊肾病（PKD）基础的双等位基因PKD 1和PKD 2变体的患病率。所有样本均通过PKD 1和PKD 2基因的桑格测序和多重连接依赖性探针扩增（MLPA）和/或包括PKHD 1和HNF 1B在内的15个额外囊性基因的下一代测序面板进行检测。2例患者接受了外显子组或基因组测序。在30例PKD-VEO婴儿中检测到可能的致病PKD 1或PKD 2变异体，其中16例在子宫内出现。21/30例（70%）患儿有2个PKD双等位基因突变，1例患儿有PKD 2双等位基因突变，2例患儿有PKD 1/PKD 2双基因突变。有13个家族（43%）没有已知的ADPKD家族史，6个家族（23%）证实了新发致病性变异。我们报告了PKD-VEO婴儿中低形态PKD 1变异和可能的双等位基因疾病的高患病率，这对生殖咨询有重要意义。然而，在PKD-VEO和其他受类似变异影响的疾病中，使用当前的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）变异分类指南对这些变异进行诊断解释和报告仍然具有挑战性。
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). 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. 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%). 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.
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