Unraveling the Genotype-Phenotype Landscape of Kleefstra Syndrome Through

Background and Objectives: Kleefstra syndrome type 1 (KLEFS1) is a rare neurodevelopmental disorder caused by pathogenic variants in Methods: This retrospective study included patients with KLEFS1 evaluated at Seoul National University Hospital between January 2022 and April 2025. Genetic diagnoses were made using chromosomal microarray or whole-exome or whole-genome sequencing, and clinical data were extracted from medical records. To enhance statistical power, we conducted a joint analysis with established cohorts of at least 30 clinically characterized patients. Results: Among the 15 patients with KLEFS1, 14 (93.3%) exhibited GDD or ID, with frequent comorbidities such as CHDs (8/12, 66.7%), orthopaedic manifestations (6/12, 50.0%), epilepsy (6/15, 40.0%), and sleep problems (4/11, 36.4%). Brain MRI revealed abnormalities in 10 of the 12 patients (83.3%), including pituitary anomalies in 2 (16.7%). By combining our data with recently published multicenter international cohorts, we assessed genotype-phenotype correlations by comparing the clinical features of 202 patients with different variant subtypes. Patients with multigene deletions had a significantly higher prevalence of CHDs (53.5% vs 25.8%, Discussion: Our study showed that patients with multigene deletions are significantly more likely to exhibit multiorgan involvement, including CHDs, cortical visual impairments, microcephaly, corpus callosum abnormalities, and hearing impairments, compared with those with SNVs or indels, emphasizing the importance of genotype-informed management. We report pituitary gland abnormalities in KLEFS1, expanding the phenotypic and neuroimaging spectrum of KLEFS1. The patient showing regression in their 30s necessitates long-term, comprehensive studies to support care.