Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

解释具有神经认知表型的男性中母系遗传的 X 染色体变异的重要性仍然对临床遗传学家和诊断实验室提出挑战。在此，我们报告了来自 9 个家族的 14 名男性，其 Xq13.2-q13.3 基因座有重复，具有共同的面部表型、智力障碍 (ID)、独特的行为特征，以及两例癫痫症。所有接受测试的携带者母亲的智力均正常。这种重复出现在三名可以进行祖父母测试的母亲身上。在一个家庭中，重复现象与 ID 分离到了三代人中。 RLIM是我们重复基因中唯一共有的基因。然而，侧翼基因在一些但并非所有受影响个体中复制，包括大脑表达基因NEXMIF 、 SLC16A2和长非编码 RNA 基因FTX 。 RLIM侧翼基因对具有不同大小重复的个体表型的贡献尚未完全解决。最近发现RLIM中的错义变异会导致男性 X 连锁 ID，而杂合女性通常智力正常，但 X 染色体失活高度倾斜。我们检测到来自 5 个重复家族的 7 名受影响男性的细胞中RLIM mRNA 和蛋白质水平持续显着增加。随后对 MDM2（RLIM E3 连接酶活性的靶标之一）的分析显示，受影响雄性的细胞中存在一致的下调。所有携带者母亲均表现出正常的RLIM mRNA 水平，并且 X 染色体失活高度倾斜。我们建议在 Xq13.2-13 处重复。3 包括RLIM在半合子男性中引起可识别但轻微的神经认知表型。