Unraveling the Genotype-Phenotype Landscape of Kleefstra Syndrome Through EHMT1 Variant Analysis.
- 1Department of Genomic Medicine, Seoul National University Hospital, Republic of Korea; and.
- 2Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Republic of Korea.
Abstract
Background and objectives
Kleefstra syndrome type 1 (KLEFS1) is a rare neurodevelopmental disorder caused by pathogenic variants in EHMT1, which play a key role in epigenetic regulation. Core features include global developmental delay (GDD), intellectual disability (ID), facial dysmorphism, congenital heart defects (CHDs), and neuropsychiatric manifestations.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%, p value = 2 × 10⁻⁴), cortical visual impairment (12.5% vs 1.7%, p value = 0.004), microcephaly (37.1% vs 17.8%, p value = 0.009), corpus callosum abnormalities (17.9% vs 5.9%, p value = 0.02), and hearing impairment (39.7% vs 25.6%, p value = 0.04) than those with single-nucleotide variants (SNVs) or short insertions/deletions (indels), in addition to the previously identified features including epilepsy, constipation, and short stature. We also observed that a recurrent EHMT1 variant (p.Arg948Trp), identified in multiple unrelated patients, was linked to significant phenotypic heterogeneity, including late-onset neurocognitive regression.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.
Related
- NOTCH2 VUS Interpretation in Pediatric Cholestasis: A 365-Variant Landscape and Genotype–Phenotype Analysis of 7 Cases
- Clinical spectrum and genotype–phenotype correlations of MT-CYB-associated mitochondrial disease: from the m.15045G > A variant to the broader disease landscape
- Dynamic tissue-specific mosaicism in constitutional non-supernumerary ring chromosome 21 with a Down syndrome-like phenotype: a case report and genotype-phenotype analysis
- Novel Compound Heterozygous CEP152 Variants Associated with Atypical Seckel Syndrome 5 in a Chinese Child: Functional Characterization of a Novel Splice-Site Variant and Expansion of the Genotype-Phenotype Spectrum.
- Metabolic collapse as a mechanism of developmental regression: convergent evidence from Kleefstra syndrome FDG-PET/CT imaging and Drosophila modelling
BibTeX
@article{kim2026unraveling,
title = {{Unraveling the Genotype-Phenotype Landscape of Kleefstra Syndrome Through EHMT1 Variant Analysis.}},
author = {Jee Min Kim and Jong Ho Cha and Woojoong Kim and Soo Yeon Kim and Jung Min Ko and Byungchan Lim and Seungbok Lee and Jong-Hee Chae},
journal = {Neurology. Genetics},
year = {2026},
month = oct,
doi = {10.1212/nxg.0000000000200445},
url = {https://europepmc.org/article/MED/42899136},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Unraveling the Genotype-Phenotype Landscape of Kleefstra Syndrome Through EHMT1 Variant Analysis.
AU - Jee Min Kim
AU - Jong Ho Cha
AU - Woojoong Kim
AU - Soo Yeon Kim
AU - Jung Min Ko
AU - Byungchan Lim
AU - Seungbok Lee
AU - Jong-Hee Chae
PY - 2026
DA - 2026/10/15
JO - Neurology. Genetics
DO - 10.1212/nxg.0000000000200445
UR - https://europepmc.org/article/MED/42899136
AB - Background and objectives Kleefstra syndrome type 1 (KLEFS1) is a rare neurodevelopmental disorder caused by pathogenic variants in EHMT1, which play a key role in epigenetic regulation. Core features include global developmental delay (GDD), intellectual disability (ID), facial dysmorphism, congenital heart defects (CHDs), and neuropsychiatric manifestations.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%, p value = 2 × 10⁻⁴), cortical visual impairment (12.5% vs 1.7%, p value = 0.004), microcephaly (37.1% vs 17.8%, p value = 0.009), corpus callosum abnormalities (17.9% vs 5.9%, p value = 0.02), and hearing impairment (39.7% vs 25.6%, p value = 0.04) than those with single-nucleotide variants (SNVs) or short insertions/deletions (indels), in addition to the previously identified features including epilepsy, constipation, and short stature. We also observed that a recurrent EHMT1 variant (p.Arg948Trp), identified in multiple unrelated patients, was linked to significant phenotypic heterogeneity, including late-onset neurocognitive regression.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.
SN - 2376-7839
ER -