子宫平滑肌瘤（ULs）是常见于绝经前女性的良性平滑肌瘤。MED12、HMGA2、FH、编码SRCAP复合物亚基的基因以及涉及Cullin 3-RING E3连接酶化的基因等體細胞突變是互斥的UL驅動因素。现有的易感基因只能部分解释肌瘤的估计遗传性。在这里，我们在由233,614名白种欧洲女性组成的队列中检查了18,899个基因的功能丧失变异，并发现四个编码SRCAP复合物亚基的基因（YEATS4、ZNHIT1、DMAP1和ACTL6A）与ULs存在显著关联，特别是YEATS4和ZNHIT1，分别排名第一和第二。阳性突变状态还与诊断和子宫切除的年龄较小有关。中等穿透率的UL风险主要归因于影响SRCAP复合物的罕见非同义突变。为了更仔细地研究这种疾病表型，我们着手在我们的内部样本集合中（n = 860）鑒定影响SRCAP复合物的遗传突变，这些样本来自芬兰患有ULs的个体。我们检测到一个具有ACTL6A剪接位点突变的个体，两个具有YEATS4错义突变的个体以及带有DMAP1突变的四个个体：一个剪接位点，一个无意义突变和两个错义变异体。这些个体具有大型和/或多个UL，通常在年幼时被诊断出来，并且许多人有UL家族史。当发现體細胞第二次打击时，ACTL6A和DMAP1在腫瘤中通过體細胞突變沉默，而YEATS4则通过啟動子高甲基化沉默。肿瘤中观察到H2A.Z染色的降低，为基因组变异的致病性提供了进一步证据。我们的结果确立了编码SRCAP复合物亚基的基因失活作为中等穿透率UL易感的中心贡献者。 版权所有 © 2023 The Authors. 由Elsevier Inc.出版。保留所有权利。

Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.