Clinical characteristics and genetic analysis of four pediatric patients with Kleefstra syndrome

被引：0
作者：
Ren, Rong [1 ]
Liu, Yedan [2 ]
Liu, Peipei [2 ]
Zhao, Jing [1 ]
Hou, Mei [1 ]
Li, Shuo [3 ]
Chen, Zongbo [2 ]
Yuan, Aiyun [1 ]
机构：
[1] Qingdao Univ, Dept Neurorehabil, Affiliated Womens & Childrens Hosp, 6 Tongfu Rd, Qingdao 266000, Shandong, Peoples R China
[2] Qingdao Univ, Affiliated Hosp, Dept Pediat, 16 Jiangsu Rd, Qingdao 266000, Shandong, Peoples R China
[3] Qingdao Univ, Dept Med Genet, Affiliated Womens & Childrens Hosp, 6 Tongfu Rd, Qingdao 266000, Shandong, Peoples R China
来源：
BMC MEDICAL GENOMICS | 2024年 / 17卷 / 01期
关键词：
Kleefstra syndrome-1 (KLEFS1); Kleefstra syndrome-2 (KLEFS2); KMT2C gene; EHMT1; gene; Exome sequencing (ES); RT-qPCR; DE-NOVO; AUTISM;
D O I：
10.1186/s12920-024-02065-5
中图分类号：
Q3 [遗传学];
学科分类号：
071007 ; 090102 ;
摘要：
Background Kleefstra syndrome spectrum (KLEFS) is an autosomal dominant disorder that can lead to intellectual disability and autism spectrum disorders. KLEFS encompasses Kleefstra syndrome-1 (KLEFS1) and Kleefstra syndrome-2 (KLEFS2), with KLEFS1 accounting for more than 75%. However, limited information is available regarding KLEFS2. KLEFS1 is caused by a subtelomeric chromosomal abnormality resulting in either deletion at the end of the long arm of chromosome 9, which contains the EHMT1 gene, or by variants in the EHMT1 gene and the KMT2C gene that cause KLEFS2. Methods This study was a retrospective analysis of clinical data from four patients with KLEFS. Exome sequencing (ES) and Sanger sequencing techniques were used to identify and validate the candidate variants, facilitating the analysis of genotype-phenotype correlations of the EHMT1 and KMT2C genes. Protein structure modeling was performed to evaluate the effects of the variants on the protein's three-dimensional structure. In addition, real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were used to examine the protein and mRNA levels of the KMT2C gene. Results Two patients with KLEFS1 were identified: one with a novel variant (c.2382 + 1G > T) and the other with a previously reported variant (c.2426 C > T, p.Pro809Leu) in the EHMT1 gene. A De novo deletion at the end of the long arm of chromosome 9 was also reported. Furthermore, a patient with KLEFS2 was identified with a novel variant in the KMT2C gene (c.568 C > T, p.Arg190Ter). The RT-qPCR and western blot results revealed that the expression of the KMT2C gene was downregulated in the KLEFS2 sample. Conclusion This study contributes to the understanding of both KLEFS1 and KLEFS2 by identifying novel variants in EHMT1 and KMT2C genes, thereby expanding the variant spectrum. Additionally, we provide the first evidence of how a KMT2C variant leads to decreased gene and protein expression, enhancing our understanding of the molecular mechanisms underlying KLEFS2. Based on these findings, children exhibiting developmental delay, hypotonia, distinctive facial features, and other neurodevelopmental abnormalities should be considered for ES to ensure early intervention and treatment.
引用
收藏
页数：12
相关论文
共 35 条
  • [21] Colijn M.A., Lakusta C.M., Marcadier J.L., Psychosis and autism without functional regression in a patient with Kleefstra syndrome, Psychiatr Genet, 33, 1, pp. 34-36, (2023)
  • [22] Koemans T.S., Kleefstra T., Chubak M.C., Stone M.H., Reijnders M.R.F., de Munnik S., Et al., DR FitzPatrick editor 2017 Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder, Plos Genet, 13, 10
  • [23] Fear V.S., Forbes C.A., Anderson D., Rauschert S., Syn G., Shaw N., Et al., Functional validation of variants of unknown significance using CRISPR gene editing and transcriptomics: A Kleefstra syndrome case study, Gene, 821, (2022)
  • [24] Alsaqati M., Davis B.A., Wood J., Jones M.M., Jones L., Westwood A., Et al., NRSF/REST lies at the intersection between epigenetic regulation, miRNA-mediated gene control and neurodevelopmental pathways associated with Intellectual disability (ID) and Schizophrenia, Translational Psychiatry, 12, 1, (2022)
  • [25] Frega M., Linda K., Keller J.M., Gumus-Akay G., Mossink B., van Rhijn J.R., Et al., Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling, Nat Commun, 10, 1, (2019)
  • [26] Iglesias-Ortega L., Megias-Fernandez C., Dominguez-Gimenez P., Jimeno-Gonzalez S., Rivero S., Cell consequences of loss of function of the epigenetic factor EHMT1, Cell Signal, 108, (2023)
  • [27] Zheng Y., Liu A., Wang Z.J., Cao Q., Wang W., Lin L., Et al., Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease, Brain, 142, 3, pp. 787-807, (2019)
  • [28] Wang Z.J., Zhong P., Ma K., Seo J.S., Yang F., Hu Z., Et al., Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice, Mol Psychiatry, 25, 10, pp. 2517-2533, (2020)
  • [29] Alonso A., Samanta A., van der Meij J., van den Brand L., Negwer M., Navarro Lobato I., Et al., Defensive and offensive behaviours in a Kleefstra syndrome mouse model, Anim Cogn, 26, 4, pp. 1131-1140, (2023)
  • [30] Blackburn P.R., Tischer A., Zimmermann M.T., Kemppainen J.L., Sastry S., Johnson A.E., Et al., A novel Kleefstra syndrome-associated variant that affects the conserved TPLX motif within the Ankyrin repeat of EHMT1 leads to abnormal protein folding, J Biol Chem, 292, 9, pp. 3866-3876, (2017)
1234