Novel germline variants in KMT2C in Chinese patients with Kleefstra syndrome-2

Qi Yang; Qiang Zhang; Sheng Yi; Shujie Zhang; Shang Yi; Xunzhao Zhou; Zailong Qin; Biyan Chen; Jingsi Luo

doi:10.3389/fneur.2024.1340458

Novel germline variants in KMT2C in Chinese patients with Kleefstra syndrome-2

Front Neurol. 2024 Jan 31:15:1340458. doi: 10.3389/fneur.2024.1340458. eCollection 2024.

Authors

Qi Yang^#^{1

2}, Qiang Zhang^#^{1

2}, Sheng Yi^{1

2}, Shujie Zhang^{1

2}, Shang Yi^{1

2}, Xunzhao Zhou^{1

2}, Zailong Qin^{1

2}, Biyan Chen^{1

2}, Jingsi Luo^{1

2

3}

Affiliations

¹ Guangxi Key Laboratory of Birth Defects Research and Prevention, Guangxi Key Laboratory of Reproductive Health and Birth Defects Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
² Department of Genetic and Metabolic Central Laboratory, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
³ Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.

^# Contributed equally.

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.

Keywords: KMT2C; Kleefstra syndrome-2; genotype-phenotype correlation; novel variants; whole-exome sequencing.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by the Health Department of Guangxi Province (Grant Nos. Z-A20220256 and Z-2016702), the Guangxi Medical and Health Appropriate Technology Development and Promotion Application (S2020060), and the Guangxi Clinical Research Center for Pediatric Diseases (Guike AD22035121).