Global developmental delay and a de novo deletion of the 16p13.13 region.

Many rare genetic variants are associated with the risk of atypical neurodevelopmental trajectories. In this study, we report a patient with developmental delay, autistic traits and multiple congenital anomalies, including congenital heart anomalies and orofacial cleft, with a 0.832 Mb de novo deletion of the 16p13.13 region classified as a variant of uncertain significance. Comparison of similar sized deletions and duplications overlapping the same genes in the DECIPHER database, revealed seven reports of copy number variants (CNVs), four duplications and three deletions. A neurodevelopmental phenotype including learning disability and intellectual disability was noted in some of the DECIPHER entries where phenotype was provided. Although the association between a deletion in this region and an atypical neurodevelopmental trajectory remains to be elucidated, the overlapping CNVs with neurodevelopmental phenotypes suggests possible candidate genes within the 16p13.13 region.

Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene.

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.

Supporting Children With Neurodevelopmental Disorders During the COVID-19 Pandemic.

Families of children with neurodevelopmental disorders are especially vulnerable during the COVID-19 pandemic. Physical distancing requirements and closure of schools and services in the context of the COVID-19 pandemic are likely challenging to everyone but may be particularly impactful for families with children with neurodevelopmental disorders ([NDDs], eg, intellectual disability, attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD]). Although a small number of children may experience less stress or anxiety due to reduced social and academic expectations,1 for many children with NDDs, and particularly those with ASD, carefully developed behavioral and environmental supports, and consistent and predictable routines and expectations, are vital for their mental well-being.2 Consequently, abrupt discontinuation of these supports during quarantine and prolonged isolation creates a real risk for behavioral exacerbations in this vulnerable population.3-6 Possible consequences for family members include physical and mental strain,7 whereas for the child with an NDD, increased emotional distress and challenging behavior may create safety concerns and the need for hospitalization.4,6 Children with NDDs may be at increased risk for COVID and COVID-related complications,8 emphasizing the need for preventive and/or crisis behavioral health care availability outside of emergency and hospital settings.

Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants.

De novo loss-of-function (LoF) variants in the KMT2A gene are associated with Wiedemann-Steiner Syndrome (WSS). Recently, de novo KMT2A variants have been identified in sequencing studies of cohorts of individuals with neurodevelopmental disorders (NDDs). However, most of these studies lack the detailed clinical information required to determine whether those individuals have isolated NDDs or WSS (i.e. syndromic NDDs). We performed thorough clinical and neurodevelopmental phenotyping on six individuals with de novo KMT2A variants. From these data, we found that all six patients met clinical criteria for WSS and we further define the neurodevelopmental phenotypes associated with KMT2A variants and WSS. In particular, we identified a subtype of Autism Spectrum Disorder (ASD) in five individuals, characterized by marked rigid, repetitive and inflexible behaviours, emotional dysregulation, externalizing behaviours, but relative social motivation. To further explore the clinical spectrum associated with KMT2A variants, we also conducted a meta-analysis of individuals with KMT2A variants reported in the published literature. We found that de novo LoF or missense variants in KMT2A were significantly more prevalent than predicted by a previously established statistical model of de novo mutation rate for KMT2A. Our genotype-phenotype findings better define the clinical spectrum associated with KMT2A variants and suggest that individuals with de novo LoF and missense variants likely have a clinically unrecognized diagnosis of WSS, rather than isolated NDD or ASD alone. This highlights the importance of a clinical genetic and neurodevelopmental assessment for individuals with such variants in KMT2A.