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

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 () on chromosome 9q34.3 or pathogenic variants in gene, and Kleefstra syndrome-2 (KLEFS2, OMIM: 617768), caused by pathogenic variants in the gene. More than 100 cases of KLEFS1 have been reported with pathogenic variants in the 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 variants through whole-exome sequencing (WES). We identified five different variants of the gene in these patients: c.9166C>T (p.Gln3056), c.9232_9247delCAGCGATCAGAACCGT (p.Gln3078fs13), c.5068dupA (p.Arg1690fs10), c.10815_10819delAAGAA (p.Lys3605fs7), and c.6911_6912insA (p.Met2304fs8). 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 variants presented with a wide range of phenotypic defects and an extremely variable phenotype. We concluded that the core phenotypes associated with 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.