De novo mutations in ATAD3A (ATPase family AAA-domain containing protein 3A) were recently found to cause a neurological syndrome with developmental delay, hypotonia, spasticity, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. Using whole-exome sequencing, we identified a dominantly inherited heterozygous variant c.1064G > A (p.G355D) in ATAD3A in a mother presenting with hereditary spastic paraplegia (HSP) and axonal neuropathy and her son with dyskinetic cerebral palsy, both with disease onset in childhood. HSP is a clinically and genetically heterogeneous disorder of the upper motor neurons. Symptoms beginning in early childhood may resemble spastic cerebral palsy. The function of ATAD3A, a mitochondrial inner membrane AAA ATPase, is yet undefined. AAA ATPases form hexameric rings, which are catalytically dependent on the co-operation of the subunits. The dominant-negative patient mutation affects the Walker A motif, which is responsible for ATP binding in the AAA module of ATAD3A, and we show that the recombinant mutant ATAD3A protein has a markedly reduced ATPase activity. We further show that overexpression of the mutant ATAD3A fragments the mitochondrial network and induces lysosome mass. Similarly, we observed altered dynamics of the mitochondrial network and increased lysosomes in patient fibroblasts and neurons derived through differentiation of patient-specific induced pluripotent stem cells. These alterations were verified in patient fibroblasts to associate with upregulated basal autophagy through mTOR inactivation, resembling starvation. Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including HSP, with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity.

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Myocardial dysfunction is a known risk factor for morbidity and mortality in hypoplastic left heart syndrome (HLHS). Variants in some transcription factor and contractility genes, which are known to cause cardiomyopathy, have previously been associated with impaired right ventricular function in some HLHS patients. The care of HLHS patients is resource demanding. Identifying genetic variants associated with myocardial dysfunction would be helpful in tailoring the follow-up and therapeutic strategies. We tested whether a commercial cardiomyopathy gene panel could serve as a diagnostic tool in a Finnish cohort of HLHS patients with impaired right ventricular function to identify potentially pathogenic variants associated with poor prognosis. None of the patients had pathogenic or likely pathogenic variants in the studied cardiomyopathy-associated genes. Thus, our approach of performing a cardiomyopathy gene panel to identify pathogenic variants as directly causal or as modifiers for worse outcomes in hypoplastic left heart syndrome is not useful in clinical practice at the moment.

Secondary organic aerosol (SOA) impact climate by scattering and absorbing radiation and contributing to cloud formation. SOA models are based on studies of simplified chemical systems that do not account for the chemical complexity in the atmosphere. This study investigated SOA formation from a mixture of real Scots pine (Pinus sylvestris) emissions including a variety of monoterpenes and sesquiterpenes. SOA generation was characterized from different combinations of volatile compounds as the plant emissions were altered with an herbivore stress treatment. During active herbivore feeding, monoterpene and sesquiterpene emissions increased, but SOA mass yields decreased after accounting for absorption effects. SOA mass yields were controlled by sesquiterpene emissions in healthy plants. In contrast, SOA mass yields from stressed plant emissions were controlled by the specific blend of monoterpene emissions. Conservative estimates using a box model approach showed a 1.5- to 2.3-fold aerosol enhancement when the terpene complexity was taken into account. This enhancement was relative to the commonly used model monoterpene, "alpha-pinene". These results suggest that simplifying terpene complexity in SOA models could lead to underpredictions in aerosol mass loading.

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.