Clinical phenotypes and molecular findings in ten Chinese patients with Kleefstra Syndrome Type 1 due to EHMT1 defects

Kleefstra syndrome type 1 (KS1, OMIM#610253) is a rare autosomal-dominant Mendelian disorder due to heterozygous mutations in the EHMT1 gene or heterozygous deletion of genomic segment of 9q34.3(9qdel). Neurodevelopmental disorder (NDD), intellectual disability (ID) and childhood-onset hypotonia are the well-known phenotypes of KS1. However, these findings were all investigated based on western patients with KS1. KS1 patients were diagnosed by genetic tests. The clinical data was collected and the phenotypes were standardized by compared with patients that previously reported. In silico, conservational and protein structural analysis were performed to assessment the missense variants. Ten patients from unrelated families were diagnosed as KS1, who all had NDD and seven of them had global developmental delay (GDD) with significant personal-social disabilities. Among the ten patients, only one (1/10) patient showed neonatal or infantile obesity. The other nine patients were heterozygous variations, including three missense mutations (p.Glu235Gly, p.Asp903Gly, and p.Leu943Pro), three frameshifting mutations (p.Asn1106Lysfs*71, p.Asn1055Tyrfs*121, and p.Lys288Argfs*20), one nonsense mutation (p.Arg246*), one slice site mutation (c.3540+2T > C) and one 9q34.3 deletion in gene of EHMT1. Furthermore, missense mutations showed potential pathogenicity analyzed by in silico. We demonstrated that the clinical features in Chinese patients with KS1 were due to EHMT1 defects. We also reported seven novel variants which enriched the mutation spectrum and provided a good understanding of the pathogenesis of KS1.