■CorneliadeLange综合征(CdLS)是由包括NIPBL在内的内聚基因变异引起的遗传性疾病,SMC1A,SMC3、RAD21和HDAC8。根据2018年的共识声明,临床评分≥11分的患者可诊断为CdLS。然而,非内聚基因而非内聚基因中的一些变异可以表现为CdLS的表型。
■这项研究描述了非内聚基因的六个变体(KDM6A,KMT2D,KMT2AANKRD11和UBE2A),并评估了11分量表标准在CdLS临床诊断中的可靠性。
■对6例具有CdLS特征的患者进行了全外显子组测序(WES)。总结了40例先前报道的具有由非内聚基因变异引起的CdLS特征的患者和34例先前报道的NIPBL变异的患者的表型和基因型谱。在具有NIPBL变异的患者与具有非粘附素基因变异的患者之间进行临床评分比较。
■在6名患者中发现了非内聚基因的变异[KMT2A(n=2),KMT2D,ANKRD11,KDM6A,和UBE2A]。其中,四种变体(KMT2Ac.7789C>T,ANKRD11c.1757_1776del,KDM6Ac.655-1G>A,和UBE2Ac.439C>T)是新颖的。结合以前报道的病例,现在报道了46例由20种非内聚基因变异引起的CdLS表型患者。从这个总队列中,ANKRD11队列患者的平均临床评分,SETD5队列,AFF4队列在统计学上低于NIPBL队列(8.92±1.77vs.12.23±2.58,7.33±2.52vs.12.23±2.58,5.33±1.53vs.12.23±2.58;p<0.05)。KMT2A队列的平均临床评分,EP300队列,NIPBL队列与(11±2.19vs.12.23±2.58,10±4.58vs.12.23±2.58;p>0.05)。
■我们在6名具有CdLS表型的中国患者中描述了4种非内聚基因的新变体。值得注意的是,三个基因(KMT2D,KDM6A,和UBE2A)引起CdLS的特征从未被报道过。拟议的CdLS临床标准需要更新和完善,只要WES是必要的,以确认CdLS的诊断。我们的研究扩展了具有CdLS特征的患者的非内聚遗传变异的光谱。
UNASSIGNED: Cornelia de Lange syndrome (CdLS) is a genetic disorder caused by variants in cohesion genes including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. According to the 2018 consensus statement, a patient with clinical scored ≥ 11 points could be diagnosed as CdLS. However, some variants in non-cohesion genes rather than cohesion genes can manifest as phenotypes of CdLS.
UNASSIGNED: This study describes six variants of non-cohesion genes (KDM6A, KMT2D, KMT2A ANKRD11, and UBE2A), and assesses the reliability of 11-points scale criteria in the clinical diagnosis of CdLS.
UNASSIGNED: Whole-exome sequencing (WES) was performed on six patients with features of CdLS. Phenotypic and genotypic spectra of 40 previously reported patients with features of CdLS caused by non-cohesion genes variants and 34 previously reported patients with NIPBL variants were summarized. Clinical score comparison among patients with NIPBL variants versus those with variants in non-cohesin genes was performed.
UNASSIGNED: Variants in non-cohesion genes were found in six patients [KMT2A (n = 2), KMT2D, ANKRD11, KDM6A, and UBE2A]. Of them, four variants (KMT2A c.7789C > T, ANKRD11 c.1757_1776del, KDM6A c.655-1G > A, and UBE2A c.439C > T) were novel. Combining with previously reported cases, 46 patients with phenotypes of CdLS caused by variants in 20 non-cohesion genes are now reported. From this total cohort, the average clinical score of patients in ANKRD11 cohort, SETD5 cohort, and AFF4 cohort was statistically lower than those in NIPBL cohort (8.92 ± 1.77 vs. 12.23 ± 2.58, 7.33 ± 2.52 vs. 12.23 ± 2.58, 5.33 ± 1.53 vs. 12.23 ± 2.58; p < 0.05). The average clinical score of KMT2A cohort, EP300 cohort, and NIPBL cohort had not significantly different from (11 ± 2.19 vs. 12.23 ± 2.58, 10 ± 4.58 vs. 12.23 ± 2.58; p > 0.05).
UNASSIGNED: We described 4 novel variants of non-cohesion genes in six Chinese patients with phenotypes of CdLS. Of note, three genes (KMT2D, KDM6A, and UBE2A) causing features of CdLS have never been reported. The proposed clinical criteria for CdLS needed to be updated and refined, insofar as WES was necessary to confirm the diagnosis of CdLS. Our study expanded the spectra of non-cohesion genetic variations in patients with features of CdLS.