Novel Phenotypes and Genotype–Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome

ABSTRACT Kleefstra syndrome (KLEFS) is a genetic neurodevelopmental disorder caused by haploinsufficiency of EHMT1 . The full spectrum of clinical features and genotype–phenotype correlations is currently not fully understood. We performed a retrospective chart review of patients with KLEFS evaluated at the Boston Children's Hospital Kleefstra Clinic. There were 65 individuals (40 females, 25 males, mean age 9.3 years). 17% had large 9q34 deletions (≥ 1 Mb), 29% had small 9q34 deletions (< 1 Mb), and 54% had sequence variants. Global developmental delay (GDD) or intellectual disability (ID) was present in 77%. Behavioral disorders, such as autism spectrum disorder (38%), were common. Epilepsy affected 15%. Systemic health issues included structural cardiac defects (40%), hearing loss (32%), and constipation (31%). Novel features including subgroups with significant motor impairment (24%) and refractory epilepsy (9%), as well as small numbers with opsoclonus‐like eye movements ( n = 2), thrombocytopenia ( n = 2), progressive cerebral atrophy ( n = 1), and adrenal carcinoma ( n = 1). 9q34 deletion subgroups had higher rates of GDD/ID ( p = 0.037), significant motor impairment ( p = 0.01), epilepsy ( p = 0.004), and cortical visual impairment ( p = 0.003) compared to the subgroup with sequence variants. This information may be used to improve clinical care as well as inform research and future therapeutic initiatives.