An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

Characteristics of children with autism and unspecified intellectual developmental disorder (intellectual disability) presenting with severe self-injurious behaviours.

Objective: This study aims to delineate the characteristics of severe self-injurious behaviors (SIB) in a cohort of children with autism and unspecified intellectual developmental disorder (UIDD) (intellectual disability) and examine potential risk factors for developing SIB. Methods: A retrospective chart review studied characteristics of severe SIB in 30 children with autism spectrum disorder (ASD) and UIDD referred to a tertiary care center. Characteristics examined include genetic syndromes, brain MRI abnormalities, verbal ability, adaptive functioning, SIB frequency and severity, age of onset, number of psychopharmacological agents, irritability, hyperactivity, stereotypy, psychiatric and physical comorbidities, among others. Descriptive and bivariate analysis were applied to explore potential relationships between factors. Results: Children with severe SIB exhibit this behaviour with high frequency, inflicting moderate to severe injury. Most children in the study sample are non-verbal and have ASD (93.3%; n = 28) with psychiatric (96.7%; n = 29) and physical (90%; n = 27) comorbidities. Overall SIB improvement using the Clinical Global Impression, Improvement Score (CGI-I) was 3.0 (minimally improved). A minority were much or very much improved following appropriate intervention. Conclusions: The severity of SIB is much higher in this sample than previously noted in the literature. Severe SIB is associated with ADHD, early onset mood disorders, tics, avoidant restrictive food intake disorder and Obsessive-Compulsive Disorder.