Neurology. Genetics · 2026
Unraveling the Genotype-Phenotype Landscape of Kleefstra Syndrome Through EHMT1 Variant Analysis.
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Kim Jee Min, Cha Jong Ho, Kim Woojoong, Kim Soo Yeon, Ko Jung Min, Lim Byungchan, Lee Seungbok, Chae Jong-Hee
Аннотация
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.
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.