Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.

Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link.

AIMS: Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown. METHODS AND RESULTS: Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands and GenIDA (163 patients) based on worldwide surveys of patient families. Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median [interquartile range (IQR)] age was considerably younger: GenIDA/Radboudumc at 10/13.5 (12/13) years, respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one atrial fibrillation (AF), two with supraventricular tachycardias, and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia (AT). In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (three AF and one AT) without structural heart disease. CONCLUSION: In addition to a high prevalence of CHD, evolving data reveal early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.

Expanding the Neuropsychological Phenotype of KAT6B Disorders: Overlapping Features with KAT6A Syndrome.

KAT6B and KAT6A belong to the MYST family of lysine acetyltransferases, and regulate gene expression via histone modification. Although both proteins share similar structure and epigenetic regulatory functions, it remains unclear if KAT6A/6B mutation disorders, both very rare conditions, yield the same neurocognitive presentation and thus benefit from similar treatment approaches. This study provides a preliminary overview of neuropsychological functioning of 13 individuals with KAT6B disorder (Mean age = 9.01 years, SD = 5.46), which was compared to that of a recently published sample of 15 individuals with KAT6A syndrome (Mean age = 10.32 years, SD = 4.12). Participants completed a neuropsychological test battery to assess non-verbal cognition, and caregivers completed a series of standardized rating inventories to assess daily behavioral functioning. Results reveal those with KAT6B disorders present with severe adaptive deficits (92.3%) and autism-related behaviors (83.3%), juxtaposed with relatively low concerns with externalizing behaviors (7.6%), a pattern shared by the KAT6A group. Those with KAT6B disorders present with high levels of autistic features, including reduced affiliative interest, whereas social motivation is less affected within the KAT6A group. Overall, the levels of impairment in nonverbal cognition and receptive language were comparable among those with KAT6B disorders, a trend also seen in the KAT6A group. In brief, KAT6B and KAT6A disorders yield analogous neuropsychological profiles. Findings implicate common molecular pathophysiological mechanisms for these epigenetic disorders, such that similar therapies may have shared effect across diseases.

Neuropsychological profile associated with KAT6A syndrome: Emergent genotype-phenotype trends.

BACKGROUND: KAT6A (Arboleda-Tham) syndrome is a Mendelian disorder of the epigenetic machinery caused by pathogenic variants in the lysine acetyltransferase 6 A (KAT6A) gene. Intellectual disability and speech/language impairment (e.g., minimally verbal) are common features of the disorder, with late-truncating variants associated with a more severe form of intellectual disability. However, much of the cognitive phenotype remains elusive given the dearth of research. PARTICIPANTS AND METHODS: This study examined non-verbal and social skills of 15 individuals with molecularly-confirmed diagnoses of KAT6A syndrome (Mean age = 10.32 years, SD = 4.12). Participants completed select subtests from the DAS-II, the NEPSY-II, and the Beery Buktenica Developmental Test of Visual Motor Integration 6th Edition, and their caregivers completed an assortment of behavior rating inventories. RESULTS: Findings suggest global cognitive impairment with nonverbal cognition scores similar to those for receptive language. Autism-related features, particularly restricted interests and repetitive behaviors, and broad adaptive deficits were common in our sample juxtaposed with a relatively strong social drive and low frequency of internalizing and externalizing behavioral problems. A general trend of lower performance scores on nonverbal and receptive language measures was observed among those with protein-truncating variants vs. missense variants; however, no effect was observed on caregiver rating inventories of daily behaviors. Late and early truncating variants yielded comparable neuropsychological profiles. CONCLUSIONS: Overall, study results show the cognitive phenotype of KAT6A syndrome includes equally impaired nonverbal cognition and receptive language functioning, paired with relatively intact social drive and strengths in behavior regulation. Emergent genotype-phenotype correlations suggest cognition may be more affected in protein-truncating than missense mutations although similar neurobehavioral profiles were observed.

Assessing remission in major depressive disorder using a functional-structural data fusion pipeline: A CAN-BIND-1 study.

Neural network-level changes underlying symptom remission in major depressive disorder (MDD) are often studied from a single perspective. Multimodal approaches to assess neuropsychiatric disorders are evolving, as they offer richer information about brain networks. A FATCAT-awFC pipeline was developed to integrate a computationally intense data fusion method with a toolbox, to produce a faster and more intuitive pipeline for combining functional connectivity with structural connectivity (denoted as anatomically weighted functional connectivity (awFC)). Ninety-three participants from the Canadian Biomarker Integration Network for Depression study (CAN-BIND-1) were included. Patients with MDD were treated with 8 weeks of escitalopram and adjunctive aripiprazole for another 8 weeks. Between-group connectivity (SC, FC, awFC) comparisons contrasted remitters (REM) with non-remitters (NREM) at baseline and 8 weeks. Additionally, a longitudinal study analysis was performed to compare connectivity changes across time for REM, from baseline to week-8. Association between cognitive variables and connectivity were also assessed. REM were distinguished from NREM by lower awFC within the default mode, frontoparietal, and ventral attention networks. Compared to REM at baseline, REM at week-8 revealed increased awFC within the dorsal attention network and decreased awFC within the frontoparietal network. A medium effect size was observed for most results. AwFC in the frontoparietal network was associated with neurocognitive index and cognitive flexibility for the NREM group at week-8. In conclusion, the FATCAT-awFC pipeline has the benefit of providing insight on the 'full picture' of connectivity changes for REMs and NREMs while making for an easy intuitive approach.

An empirical analysis of structural neuroimaging profiles in a staging model of depression.

We examine structural brain characteristics across three diagnostic categories: at risk for serious mental illness; first-presenting episode and recurrent major depressive disorder (MDD). We investigate whether the three diagnostic groups display a stepwise pattern of brain changes in the cortico-limbic regions. Integrated clinical and neuroimaging data from three large Canadian studies were pooled (total n = 622 participants, aged 12-66 years). Four clinical profiles were used in the classification of a clinical staging model: healthy comparison individuals with no history of depression (HC, n = 240), individuals at high risk for serious mental illness due to the presence of subclinical symptoms (SC, n = 80), first-episode depression (FD, n = 82), and participants with recurrent MDD in a current major depressive episode (RD, n = 220). Whole-brain volumetric measurements were extracted with FreeSurfer 7.1 and examined using three different types of analyses. Hippocampal volume decrease and cortico-limbic thinning were the most informative features for the RD vs HC comparisons. FD vs HC revealed that FD participants were characterized by a focal decrease in cortical thickness and global enlargement in amygdala volumes. Greater total amygdala volumes were significantly associated with earlier onset of illness in the FD but not the RD group. We did not confirm the construct validity of a tested clinical staging model, as a differential pattern of brain alterations was identified across the three diagnostic groups that did not parallel a stepwise clinical staging approach. The pathological processes during early stages of the illness may fundamentally differ from those that occur at later stages with clinical progression.

KMT2D Deficiency Causes Sensorineural Hearing Loss in Mice and Humans.

Individuals with Kabuki syndrome type 1 (KS1) often have hearing loss recognized in middle childhood. Current clinical dogma suggests that this phenotype is caused by frequent infections due to the immune deficiency in KS1 and/or secondary to structural abnormalities of the ear. To clarify some aspects of hearing loss, we collected information on hearing status from 21 individuals with KS1 and found that individuals have both sensorineural and conductive hearing loss, with the average age of presentation being 7 years. Our data suggest that while ear infections and structural abnormalities contribute to the observed hearing loss, these factors do not explain all loss. Using a KS1 mouse model, we found hearing abnormalities from hearing onset, as indicated by auditory brainstem response measurements. In contrast to mouse and human data for CHARGE syndrome, a disorder possessing overlapping clinical features with KS and a well-known cause of hearing loss and structural inner ear abnormalities, there are no apparent structural abnormalities of the cochlea in KS1 mice. The KS1 mice also display diminished distortion product otoacoustic emission levels, which suggests outer hair cell dysfunction. Combining these findings, our data suggests that KMT2D dysfunction causes sensorineural hearing loss compounded with external factors, such as infection.