Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

Background: Sudden unexpected death in epilepsy (SUDEP) causes significant mortality, affecting approximately 1 in 1000 people with epilepsy. Clinical and preclinical studies have identified severe seizures, bradycardia, apnea, severe postictal hypoxia, and sleep deficiency that emerge prior to SUDEP and thus may represent temporal biomarkers. The metabolic ketogenic diet (KD) therapy increases longevity in preclinical SUDEP models. Here, the hypothesis that KD therapy would determine whether the emergent sleep deficiency, bradycardia, apnea and/or hypoxemia persist as temporal biomarkers in preclinical SUDEP was tested. Methods: Kv1.1 knockout (KO) mice, a preclinical SUDEP model, and wild-type littermates were weaned onto a standard diet (SD) or treated with KD. In separate cohorts, approximately every 10 days, seizures and sleep architecture were recorded with electroencephalography–electromyography (EEG-EMG), heart rate was measured with noninvasive ECGenie, apnea was assessed with noninvasive airway mechanics, and blood O₂ saturation was measured with pulse oximetry. Data were aligned from the day of sudden death and analyzed retrospectively. Results: KD treatment significantly increased longevity and reduced seizures, reproducing previous studies. Using retrospective analyses from the day of death, KD treatment attenuated the emergence of (i) interictal intermittent bradycardia in the last 20 days of life, (ii) apnea, and (iii) intermittent hypoxemia in the last 10 days of life. In contrast, (iv) KD treatment did not rescue REM and NREM sleep deficiencies during the last 10 days of life. Conclusions: Our findings provide novel preclinical support for KD as a candidate therapy to attenuate seizure frequency and burden, bradycardia, apnea, and hypoxemia in SUDEP. In addition, sleep deficiency persisted as a potential temporal biomarker of preclinical SUDEP; however, causality will need to be tested in future studies.