PADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement of PADI6 in infertility is well demonstrated, its role in imprinting disorders is less well established. We have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers of PADI6 variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings. Our results firmly establish the role of PADI6 in imprinting disorders. We report loss-of-function maternal-effect variants of PADI6 that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocyte PADI6 function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.

中文翻译：

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PADI6 功能丧失母体效应突变与家族性和散发性 Beckwith-Wiedemann 综合征以及多位点印记障碍相关。


PADI6 是皮质下母体复合体的组成部分，这是一组在卵母细胞细胞质中大量表达的蛋白质，但对于早期胚胎的正确发育是必需的。皮质下母体复合蛋白的母体效应变异与异质性疾病相关，包括女性不孕症、葡萄胎和多位点印记障碍的印记疾病。虽然 PADI6 与不孕症的相关性已得到充分证明，但其在印迹疾病中的作用尚不清楚。我们通过全外显子组测序分析，鉴定出四例患有多位点印记障碍的 Beckwith-Wiedemann 综合征，其母亲是 PADI6 变异携带者。计算机分析表明这些变异会导致功能丧失，而分离分析表明它们要么是隐性突变，要么是显性阴性母体效应突变。全基因组甲基化分析显示，患者（包括两个受影响的姐妹）的印记位点甲基化谱存在异质性且广泛改变，但在她们的健康兄弟姐妹中则不然。我们的结果牢固地确立了 PADI6 在印迹疾病中的作用。我们报告了 PADI6 功能丧失的母体效应变异，这些变异与后代的异质多位点印记干扰相关。两个兄弟姐妹患有贝克威斯-维德曼综合征的罕见发现表明，在某些情况下，这些变异的家族性复发风险可能很高。然而，其他谱系的异质表型表明卵母细胞 PADI6 功能的改变导致甲基化印记的随机维持，对早期胚胎健康产生不可预测的后果。