PDF(Pubmed)
Abstract：
Kleefstra syndrome (KLEFS) refers to a rare inherited neurodevelopmental disorder characterized by intellectual disability (ID), language and motor delays, behavioral abnormalities, abnormal facial appearance, and other variable clinical features. KLEFS is subdivided into two subtypes: Kleefstra syndrome-1 (KLEFS1, OMIM: 610253), caused by a heterozygous microdeletion encompassing the Euchromatic Histone Lysine Methyltransferase 1 (EHMT1) gene on chromosome 9q34.3 or pathogenic variants in the EHMT1 gene, and Kleefstra syndrome-2 (KLEFS2, OMIM: 617768), caused by pathogenic variants in the KMT2C gene. More than 100 cases of KLEFS1 have been reported with pathogenic variants in the EHMT1 gene. However, only 13 patients with KLEFS2 have been reported to date. In the present study, five unrelated Chinese patients were diagnosed with KLEFS2 caused by KMT2C variants through whole-exome sequencing (WES). We identified five different variants of the KMT2C gene in these patients: c.9166C>T (p.Gln3056*), c.9232_9247delCAGCGATCAGAACCGT (p.Gln3078fs*13), c.5068dupA (p.Arg1690fs*10), c.10815_10819delAAGAA (p.Lys3605fs*7), and c.6911_6912insA (p.Met2304fs*8). All five patients had a clinical profile similar to that of patients with KLEFS2. To analyze the correlation between the genotype and phenotype of KLEFS2, we examined 18 variants and their associated phenotypes in 18 patients with KLEFS2. Patients carrying KMT2C variants presented with a wide range of phenotypic defects and an extremely variable phenotype. We concluded that the core phenotypes associated with KMT2C variants were intellectual disability, facial dysmorphisms, language and motor delays, behavioral abnormalities, hypotonia, short stature, and weight loss. Additionally, sex may be one factor influencing the outcome. Our findings expand the phenotypic and genetic spectrum of KLEFS2 and help to clarify the genotype-phenotype correlation.
摘要：
Kleefstra综合征（KLEFS）是一种罕见的遗传性神经发育障碍，以智力障碍（ID）为特征，语言和运动延迟，行为异常,异常的面部外观，和其他可变的临床特征。KLEFS分为两个亚型：Kleefstra综合征-1（KLEFS1，OMIM：610253），由9q34.3号染色体上包含Eucrochromprochleum组蛋白赖氨酸甲基转移酶1（EHMT1）基因的杂合微缺失或EHMT1基因中的致病变体引起，和Kleefstra综合征-2（KLEFS2，OMIM：617768），由KMT2C基因的致病变异引起。已经报道了超过100例KLEFS1在EHMT1基因中具有致病变体。然而,迄今仅报告了13例KLEFS2患者.在本研究中,通过全外显子组测序(WES),5例无关的中国患者被诊断为KMT2C变异引起的KLEFS2.我们在这些患者中鉴定了KMT2C基因的五种不同变体：c.9166C>T（p。Gln3056*),c.9232_9247delCAGCGATCAGAACCGT（p。Gln3078fs*13),c.5068dupA（p。Arg1690fs*10),c.10815_10819delAAGAA（p。Lys3605fs*7)，和c.6911_6912insA（p。Met2304fs*8）。所有5名患者的临床特征与KLEFS2患者相似。为了分析KLEFS2基因型和表型之间的相关性，我们检查了18例KLEFS2患者的18种变异及其相关表型。携带KMT2C变体的患者表现出广泛的表型缺陷和极其可变的表型。我们得出结论，与KMT2C变异相关的核心表型是智力障碍，面部畸形，语言和运动延迟，行为异常,低张力,身材矮小,和减肥。此外,性别可能是影响结果的一个因素。我们的发现扩展了KLEFS2的表型和遗传谱，并有助于阐明基因型-表型相关性。
